Background: Bendamustine hydrochloride (SDX-105; TreandaTM) is a multifunctional, alkylating agen... more Background: Bendamustine hydrochloride (SDX-105; TreandaTM) is a multifunctional, alkylating agent with a purine-like ring system and novel mechanisms of action that exhibits impressive single-agent activity in multiple hematologic and solid tumors. In vitro data indicate that bendamustine induces cell death as a result of both apoptosis and mitotic catastrophe, resulting in potent cell-killing activity in cancer cells that are resistant to traditional chemotherapy (alkylating and fludarabine-containing regimens). In vitro data have also demonstrated a synergistic effect with rituximab for the treatment of non-Hodgkin’s lymphomas (NHL). A Phase II multicenter study (SDX-105-02) was conducted to determine the efficacy and toxicity of the combination of bendamustine with rituximab in relapsed NHL patients. Methods: The intent-to-treat (ITT) population consists of 54 patients with relapsed indolent CD20-positive B-cell or mantle cell NHL, enrolled from 22 sites in the US and Canada. Median age of the patients was 60 years (range 40–84); 59% had follicular NHL, 6% had small lymphocytic lymphoma, 4% had lymphoplasmacytoid lymphoma, 4% had marginal zone lymphoma, and 17% had mantle cell lymphoma; and 72% of all patients had Stage III/IV disease. Patients relapsed from a median of 1 prior therapy. Patients received rituximab, 375 mg/m2 IV on day 1, and bendamustine, 90 mg/m2 on days 2 and 3, every 28 days for 4–6 cycles. All patients received an additional dose of rituximab 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle. Results: Of the 54 ITT patients, 37% had prior treatment with rituximab. Forty-three patients are currently evaluable for response, as defined by the International Working Group. The overall response rate was 84%, with complete response in 21% and partial response in 63% of patients. The median duration of response has not yet been reached after a median follow up of 3.6 months. Minimal toxicity was observed. The most common nonhematologic toxicities included grade 1/2 gastrointestinal complications. The primary grade 3/4 hematologic toxicity was neutropenia (with no neutropenic fever), observed in 22% of patients. Grade 3/4 anemia and thrombocytopenia were observed in only 1 patient. No alopecia was observed. Conclusions: Bendamustine, administered in combination with rituximab, produced high objective response rates with minimal toxicity in patients with refractory indolent and mantle cell NHL, including patients that previously failed alkylating and fludarabine-containing regimens. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.
Background: Bendamustine HCl (TreandaTM) is a multifunctional, alkylating agent with novel mechan... more Background: Bendamustine HCl (TreandaTM) is a multifunctional, alkylating agent with novel mechanisms of action. Unlike other commonly used chemotherapeutic agents, bendamustine in vitro induces durable cell damage resulting in rapid cell death in apoptosis-resistant cancer cell lines through the apoptosis independent pathway of mitotic catastrophe. European studies have reported single-agent activity in patients with relapsed/refractory NHL, chronic lymphocytic leukemia, multiple myeloma, and breast cancer. Aim: This study evaluated the efficacy and toxicity of bendamustine in patients with NHL who have relapsed or are refractory to previous chemotherapy regimens. Patients refractory to Rituximab had disease progression within 6 months of treatment. Methods: This Phase II multicenter trial enrolled patients with relapsed indolent or transformed rituximab-refractory B-cell NHL from 17 sites in the US and Canada. Indolent histologic phenotype was seen in 84% of patients, while 16% had transformed disease. Median age of patients was 63 years (range: 38–84) and 88% had Stage III/IV disease. Patients received bendamustine 120 mg/m2 IV over 30–60 minutes, days 1 and 2, every 21 days for up to 6 cycles. Response was measured using the International Working Group criteria. Results: The intent-to-treat (ITT) population consisted of 75 heavily pretreated patients with a median of 2 prior chemotherapies. The overall objective response rate (ORR) in the ITT population was 74%; 25% had a complete response, 49% had a partial response, 12% had stable disease, and 14% had disease progression. Of 15 patients who were refractory to prior alkylator treatment (patients who progressed after at least one prior alkylator-containing therapy), 10 (67%) experienced an objective response to bendamustine. The median duration of response was 6.6 months for all patients, 9.3 months for indolent patients, and 2.4 months for transformed patients. The most frequent nonhematologic adverse events were nausea (63%), fatigue (39%), vomiting (38%), fever (25%), and diarrhea (22%). Most of these events were grade 1 or 2; alopecia and hemorrhagic cystitis were not observed. Grade 3 or 4 reversible hematologic toxicities seen included neutropenia (47%), thrombocytopenia (24%), and anemia (11%). Conclusions: Single-agent bendamustine produced durable objective responses with acceptable toxicity, despite unfavorable prognostic features, in heavily pretreated rituximab-refractory indolent and transformed NHL patients. Durable response has been seen in alkylator-resistant patients. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.
Researchers and clinicians have made great strides against many cancers but, unfortunately, not a... more Researchers and clinicians have made great strides against many cancers but, unfortunately, not all of them. Glioblastoma multiforme (GBM) remains incredibly deadly – the five-year survival rate is a meager 5%. Diffuse intrinsic pontine glioma (DIPG) is an almost universally fatal pediatric brain tumor. The five-year survival is around 2%. GBMs are generally treated with surgery and radiation. DIPG is so thoroughly embedded in the pons that surgery is impossible. Radiation can provide some small relief, and clinicians have seen some promise in CAR-T therapy. [3] However, the gains are uncertain and the cost in side effects quite high.
TPS2605 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucle... more TPS2605 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117’s efficacy in xenograft models (Colo-2...
TPS2608 Background: RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (als... more TPS2608 Background: RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progression. As a single agent, RX-5902 inhibits tumor growth and enhances survival in a variety of in vivo animal xenograft tumor models (e.g., renal, ovarian, pancreatic, melanoma). Methods: This Phase 1, open-label, multicenter study evaluates the efficacy and safety of RX-5902 in subjects with solid tumors. RX-5902 is administered orally once weekly for 3 weeks with 1 week of rest in each 4 week cycle. Dose escalation starts with an accelerated design treating 1 subject per dose followed by a standard 3 + 3 design using a modified Fibonacci sequence after the occurrence of a single Grade 2 or greater adverse event that is considered at related to RX-5902. The primary endpoint is the overall safety profile characterized by the type, frequency, severity, timing o...
RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear... more RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in vivo in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity in vitro against TNBC cell lines with an average IC50 of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G2–M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active in vivo against TNBC PDX models, and treatment resulted in a decrease in nuclear β-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFβ, and Wnt/β-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against in vitro and in vivo preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.
Background: Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progr... more Background: Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progression. RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. As a single agent, RX-5902 inhibits tumor growth and enhances survival in a variety of xenograft tumor models (e.g., pancreatic, renal, ovarian, melanoma). Methods: This Phase 1, open-label, multicenter study evaluates the efficacy and safety of RX-5902 in subjects with solid tumors. RX-5902 is administered orally 1, 3 or 5 times per week for 3 weeks with 1 week of rest in each 4 week cycle. Dose escalation starts with an accelerated design treating 1 subject per dose followed by a standard 3 + 3 design using a modified Fibonacci sequence after the occurrence of a single Grade 2 or greater adverse event that is considered at related to RX-5902. The primary endpoint is the overall safety profile characterized by the type, frequency, severity, timing of onset, duration and relationship to study therapy of any adverse events, or abnormalities of laboratory tests or electrocardiograms as well as the description of any dose limiting toxicities that occur during Cycle 1, serious adverse events, or adverse events leading to discontinuation of study treatment. Secondary endpoints include pharmacokinetic parameters (e.g., time to maximum observed concentration [T max ], maximum observed plasma concentration [C max ], trough concentration [C trough ], area under the concentration-time curve [AUC]) and Indices of anti-tumor activity (e.g., overall response rate , time to response, duration of response, and progression-free survival during treatment. Exploratory endpoints are biochemical levels of drug targets in blood and tumor samples. Eligible subjects must have confirmed histologic or cytologic evidence of metastatic or locally advanced solid neoplasm that has failed to respond to standard therapy, progressed despite standard therapy or for which standard therapy does not exist. There is no limit on the number of prior treatment regimens. NCT02003092
1097Background: RX-5902 is a novel oral anti-cancer compound targeting phosphorylated p68 (P-p68)... more 1097Background: RX-5902 is a novel oral anti-cancer compound targeting phosphorylated p68 (P-p68) (RNA helicase DDX5, a member of the DEAD box family of RNA helicases) affecting the Wnt canonical p...
2559Background: RX-0201 is a novel, oligonucleotide that binds native AKT-1 mRNA, preventing down... more 2559Background: RX-0201 is a novel, oligonucleotide that binds native AKT-1 mRNA, preventing downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, to treat metastatic clear cell renal carcinoma. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. Methods: The Phase 1b/2 proof-of-concept, multicenter, open label study is conducted in 2 stages (NCT02089334). Stage 1 is a dose-escalation Phase 1b/2 study of RX-0201 in combination with everolimus (10 mg daily). RX-0201 was given as a continuous intravenous infusion for 14 days followed by 7 days of rest. Subjects were enrolled at increasing doses of RX-0201 in a 3+3 design. The target dose of RX-0201 identified in Stage 1 is being studied further evaluated in Stage 2, which is a randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Plasma concentrations were measured in Stage 1 and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Ver...
4543Background: RX-3117 is an oral small molecule nucleoside analogue (cyclopentyl pyrimidyl nucl... more 4543Background: RX-3117 is an oral small molecule nucleoside analogue (cyclopentyl pyrimidyl nucleoside) that is activated by uridine cytidine kinase 2. RX-3117 shows efficacy in various xenograft ...
Background: BYL719 is an oral inhibitor that selectively targets the a-isoform of class l PI3K. I... more Background: BYL719 is an oral inhibitor that selectively targets the a-isoform of class l PI3K. In a first-inhuman ph1 study in mostly Western patients (pts) with PIK3CA alteration, the maximum tolerated dose for once-daily (qd) BYL719 was declared as 400 mg and preliminary antitumor activity was observed. Previous preliminary findings showed tolerability, safety, and pharmacokinetic (PK) results in dose escalation of the first-in-Japanese ph1 study. Here, we report results of the food effect on the PK profile of BYL719 at steady state, additional safety, and preliminary efficacy in Japanese pts. Methods: Pts were aged 18 years with histologically confirmed, advanced solid tumors. Pts received BYL719 qd in 28-day cycles until disease progression, unacceptable toxicity, or investigator/pts decision. The objectives in the expansion part were to assess food effect on PK profile, preliminary antitumor activity, and safety. Pts with PIK3CA alteration were selected in the expansion part and were randomized to receive BYL719 at the recommended dose 350 mg qd in fasted or fed condition on cycle 1 day 22 and cycle 2 day 1 in a crossover fashion. Pts received BYL719 1 hr following a light breakfast and continued to be fasted for 1 hr after each dose. Results: Thirty-three pts were enrolled and all pts discontinued treatment. The median duration of exposure was 71.0 days (range, 6-462). The common BYL719-related allgrade (Gr) AEs (>30%) were hyperglycemia, rash maculopapular (48.5%, each), diarrhea (45.5%), and decreased appetite (33.3%). BYL719-related Gr 3 or 4 AEs (20%) were rash maculopapular (24.2%) and hyperglycemia (21.2%). Eight pts were enrolled in the expansion part; six of them were eligible for PK analysis. The geometric mean values of dose-normalized C max and AUC 0-24 in fed state were 78% and 56% higher than those in fasted state, respectively. One pt experienced Gr 4-infected neoplasm meeting DLT criteria, 1 pt with uterus cancer and PIK3CA mutation had an unconfirmed partial response, and 18 pts had a stable disease. Conclusions: In this ph1 study of BYL719 in Japanese pts, a positive food effect and preliminary antitumor activity were observed at steady state in pts with PIK3CA mutation status.
Background: RX-0201, a novel, oligonucleotide that binds native AKT-1 mRNA, prevents downstream p... more Background: RX-0201, a novel, oligonucleotide that binds native AKT-1 mRNA, prevents downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth in vitro and is in development for the treatment of metastatic clear cell renal carcinoma Methods: The phase Ib/II proof of concept, multicenter, open label study is conducted in 2 phases. The phase Ib was a dose-escalation study of RX-0201 administered in combination with everolimus. RX-0201 was administered as a continuous intravenous infusion for 14 days followed by 7 days of rest; everolimus was administered at a starting dose of 10mg once daily. Subjects were enrolled at increasing doses of RX-0201 in a modified 3+3 design. Plasma concentrations were measured in phase Ib and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. The dose of RX-0201 identified in phase Ib is being studied further in phase II, which is the randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Results: In the Phase Ib, seven males and 3 females, (median age 61 years) were treated with 125 mg/m⁁2/day (n = 3), 200 mg/m⁁2/day (n = 4), and 250 mg/m⁁2/day (n = 3) RX-0201 in combination with 10 mg everolimus. They received 1-3 lines of therapy prior to study entry (median = 1). The most common toxicities attributed to the combination were rash, mouth ulceration, weight loss, thrombocytopenia, facial edema, fatigue, and pruritus. No significant events were attributed to RX-0201 alone. Most events (81%) were mild or moderate in severity. Based on the tolerability, 250 mg/m⁁2/day RX-0201 dose was declared the recommended phase II dose. Three subjects in the phase Ib have experienced stable disease for 383, 191, and 122 days; a tumor burden reduction of 16 and 36% was seen in 2 subjects. RX-0201 PK demonstrated a dose proportional exposure. Conclusions: RX-0201, in combination with everolimus, appears to be safe and well tolerated in patients with metastatic renal cancer at doses up to 250 mg/m⁁2/day. Randomized phase II of this trial is currently ongoing. Citation Format: Scott Tagawa, Gurkamal S. Chatta, Sumanta K. Pal, Sanjay Goel, Reza Mazhari, Callie Heaton, Ely Benaim, Neeraj Agarwal. Phase Ib/II Study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma - Phase Ib results. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT114.
646 Background: RX-0201 is a novel 20-mer oligonucleotide that binds to mRNA coding for AKT-1, pr... more 646 Background: RX-0201 is a novel 20-mer oligonucleotide that binds to mRNA coding for AKT-1, preventing AKT-1 expression and limiting the amount of downstream p-AKT. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. RX-0201, in combination with everolimus, to treat mRCC was evaluated in a Phase 1b/2 clinical study. Methods: This Phase 1b/2 study (2‐stage design, NCT02089334 ) evaluated the efficacy and safety of RX‐0201 in combination with everolimus in eligible subjects with mRCC. Eligible subjects must have had confirmed histologic or cytologic evidence of renal cancer with a clear cell component, measurable disease as defined by RECIST, received at least 1 course of therapy with a VEGFR inhibitor and progressed within 6 months of planned first dose of on study treatment. In Phase 1 subjects were enrolled at increasing doses of RX-0201 (delivered via continuous IV for 14 days) in combination with 10 mg/day everolimus in a modified 3+3 design. The target dose of RX-0201 identified in Phase 1, 250 mg/m2/day, was further evaluated in Phase 2. Primary objectives included the safety and efficacy at the recommended Phase 2 dose. The Phase 2 primary endpoint was progression free survival (PFS) benefit for at least 4.5 months. Results: Eleven subjects (7 males, 4 females) with mRCC were treated with RX-0201 (250 mg/m2/day) + everolimus (10 mg/ day) in Phase 2. The median age was 63 years, ECOG performance status at screening was 0 to 1, and 55% received ≥ 3 prior therapies. The median PFS in evaluable subjects was 4.9 months. Four subjects had stable disease after 6 months of treatment. The most frequent related adverse events ( > 15%) were G1/2 epistaxis, G3 fatigue, G1/2 nausea and G1 vomiting. Conclusions: In this mRCC population with extensive prior therapy, RX‐0201 in combination with everolimus was safe, well-tolerated, and showed promising efficacy. The results also support the therapeutic significance of the AKT-1/mTOR pathway in mRCC. Clinical trial information: NCT02089334.
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2014
Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported i... more Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/ day once-daily (QD) for 14 days plus 14 days' rest, all in 28day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21day cycles. Results Fifty-eight patients were enrolled (PIC n = 28, ECT n =30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma. Keywords Phase I-III Leukemia and lymphomas. Novel antitumor agent. Cell cycle mechanisms of anticancer drug action. Aurora A kinase inhibitor. MLN8237 ClinicalTrials.gov identifier: NCT00697346 Electronic supplementary material The online version of this article
Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside th... more Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 2 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 2 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% of evaluable subjects with a partial response rate or better. Results: As of Sep 2017, 44 subjects have been enrolled (22 females, 22 males). The median age was 68 years, ECOG performance statuses were 0 (13 subjects) and 1 (31 subjects) and 6 subjects had received 4 or more prior therapies. One subject had an unconfirmed partial response and 21 subjects met the primary endpoint of stable disease with a duration of 30-224 days. The most frequent adverse events were mild to moderate anemia (19%), mild to moderate fatigue (15%), mild to moderate diarrhea (11%), and severe anemia (9%). Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. The study continues to enroll subjects with advanced pancreatic cancer into stage 2. A phase 2 study with nab-paclitaxel in first-line patients with advanced pancreatic cancer has been started.
Background: Bendamustine hydrochloride (SDX-105; TreandaTM) is a multifunctional, alkylating agen... more Background: Bendamustine hydrochloride (SDX-105; TreandaTM) is a multifunctional, alkylating agent with a purine-like ring system and novel mechanisms of action that exhibits impressive single-agent activity in multiple hematologic and solid tumors. In vitro data indicate that bendamustine induces cell death as a result of both apoptosis and mitotic catastrophe, resulting in potent cell-killing activity in cancer cells that are resistant to traditional chemotherapy (alkylating and fludarabine-containing regimens). In vitro data have also demonstrated a synergistic effect with rituximab for the treatment of non-Hodgkin’s lymphomas (NHL). A Phase II multicenter study (SDX-105-02) was conducted to determine the efficacy and toxicity of the combination of bendamustine with rituximab in relapsed NHL patients. Methods: The intent-to-treat (ITT) population consists of 54 patients with relapsed indolent CD20-positive B-cell or mantle cell NHL, enrolled from 22 sites in the US and Canada. Median age of the patients was 60 years (range 40–84); 59% had follicular NHL, 6% had small lymphocytic lymphoma, 4% had lymphoplasmacytoid lymphoma, 4% had marginal zone lymphoma, and 17% had mantle cell lymphoma; and 72% of all patients had Stage III/IV disease. Patients relapsed from a median of 1 prior therapy. Patients received rituximab, 375 mg/m2 IV on day 1, and bendamustine, 90 mg/m2 on days 2 and 3, every 28 days for 4–6 cycles. All patients received an additional dose of rituximab 1 week prior to the first cycle of bendamustine and 4 weeks after the last cycle. Results: Of the 54 ITT patients, 37% had prior treatment with rituximab. Forty-three patients are currently evaluable for response, as defined by the International Working Group. The overall response rate was 84%, with complete response in 21% and partial response in 63% of patients. The median duration of response has not yet been reached after a median follow up of 3.6 months. Minimal toxicity was observed. The most common nonhematologic toxicities included grade 1/2 gastrointestinal complications. The primary grade 3/4 hematologic toxicity was neutropenia (with no neutropenic fever), observed in 22% of patients. Grade 3/4 anemia and thrombocytopenia were observed in only 1 patient. No alopecia was observed. Conclusions: Bendamustine, administered in combination with rituximab, produced high objective response rates with minimal toxicity in patients with refractory indolent and mantle cell NHL, including patients that previously failed alkylating and fludarabine-containing regimens. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.
Background: Bendamustine HCl (TreandaTM) is a multifunctional, alkylating agent with novel mechan... more Background: Bendamustine HCl (TreandaTM) is a multifunctional, alkylating agent with novel mechanisms of action. Unlike other commonly used chemotherapeutic agents, bendamustine in vitro induces durable cell damage resulting in rapid cell death in apoptosis-resistant cancer cell lines through the apoptosis independent pathway of mitotic catastrophe. European studies have reported single-agent activity in patients with relapsed/refractory NHL, chronic lymphocytic leukemia, multiple myeloma, and breast cancer. Aim: This study evaluated the efficacy and toxicity of bendamustine in patients with NHL who have relapsed or are refractory to previous chemotherapy regimens. Patients refractory to Rituximab had disease progression within 6 months of treatment. Methods: This Phase II multicenter trial enrolled patients with relapsed indolent or transformed rituximab-refractory B-cell NHL from 17 sites in the US and Canada. Indolent histologic phenotype was seen in 84% of patients, while 16% had transformed disease. Median age of patients was 63 years (range: 38–84) and 88% had Stage III/IV disease. Patients received bendamustine 120 mg/m2 IV over 30–60 minutes, days 1 and 2, every 21 days for up to 6 cycles. Response was measured using the International Working Group criteria. Results: The intent-to-treat (ITT) population consisted of 75 heavily pretreated patients with a median of 2 prior chemotherapies. The overall objective response rate (ORR) in the ITT population was 74%; 25% had a complete response, 49% had a partial response, 12% had stable disease, and 14% had disease progression. Of 15 patients who were refractory to prior alkylator treatment (patients who progressed after at least one prior alkylator-containing therapy), 10 (67%) experienced an objective response to bendamustine. The median duration of response was 6.6 months for all patients, 9.3 months for indolent patients, and 2.4 months for transformed patients. The most frequent nonhematologic adverse events were nausea (63%), fatigue (39%), vomiting (38%), fever (25%), and diarrhea (22%). Most of these events were grade 1 or 2; alopecia and hemorrhagic cystitis were not observed. Grade 3 or 4 reversible hematologic toxicities seen included neutropenia (47%), thrombocytopenia (24%), and anemia (11%). Conclusions: Single-agent bendamustine produced durable objective responses with acceptable toxicity, despite unfavorable prognostic features, in heavily pretreated rituximab-refractory indolent and transformed NHL patients. Durable response has been seen in alkylator-resistant patients. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.
Researchers and clinicians have made great strides against many cancers but, unfortunately, not a... more Researchers and clinicians have made great strides against many cancers but, unfortunately, not all of them. Glioblastoma multiforme (GBM) remains incredibly deadly – the five-year survival rate is a meager 5%. Diffuse intrinsic pontine glioma (DIPG) is an almost universally fatal pediatric brain tumor. The five-year survival is around 2%. GBMs are generally treated with surgery and radiation. DIPG is so thoroughly embedded in the pons that surgery is impossible. Radiation can provide some small relief, and clinicians have seen some promise in CAR-T therapy. [3] However, the gains are uncertain and the cost in side effects quite high.
TPS2605 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucle... more TPS2605 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117’s efficacy in xenograft models (Colo-2...
TPS2608 Background: RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (als... more TPS2608 Background: RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progression. As a single agent, RX-5902 inhibits tumor growth and enhances survival in a variety of in vivo animal xenograft tumor models (e.g., renal, ovarian, pancreatic, melanoma). Methods: This Phase 1, open-label, multicenter study evaluates the efficacy and safety of RX-5902 in subjects with solid tumors. RX-5902 is administered orally once weekly for 3 weeks with 1 week of rest in each 4 week cycle. Dose escalation starts with an accelerated design treating 1 subject per dose followed by a standard 3 + 3 design using a modified Fibonacci sequence after the occurrence of a single Grade 2 or greater adverse event that is considered at related to RX-5902. The primary endpoint is the overall safety profile characterized by the type, frequency, severity, timing o...
RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear... more RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in vivo in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity in vitro against TNBC cell lines with an average IC50 of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G2–M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active in vivo against TNBC PDX models, and treatment resulted in a decrease in nuclear β-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFβ, and Wnt/β-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against in vitro and in vivo preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.
Background: Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progr... more Background: Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progression. RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. As a single agent, RX-5902 inhibits tumor growth and enhances survival in a variety of xenograft tumor models (e.g., pancreatic, renal, ovarian, melanoma). Methods: This Phase 1, open-label, multicenter study evaluates the efficacy and safety of RX-5902 in subjects with solid tumors. RX-5902 is administered orally 1, 3 or 5 times per week for 3 weeks with 1 week of rest in each 4 week cycle. Dose escalation starts with an accelerated design treating 1 subject per dose followed by a standard 3 + 3 design using a modified Fibonacci sequence after the occurrence of a single Grade 2 or greater adverse event that is considered at related to RX-5902. The primary endpoint is the overall safety profile characterized by the type, frequency, severity, timing of onset, duration and relationship to study therapy of any adverse events, or abnormalities of laboratory tests or electrocardiograms as well as the description of any dose limiting toxicities that occur during Cycle 1, serious adverse events, or adverse events leading to discontinuation of study treatment. Secondary endpoints include pharmacokinetic parameters (e.g., time to maximum observed concentration [T max ], maximum observed plasma concentration [C max ], trough concentration [C trough ], area under the concentration-time curve [AUC]) and Indices of anti-tumor activity (e.g., overall response rate , time to response, duration of response, and progression-free survival during treatment. Exploratory endpoints are biochemical levels of drug targets in blood and tumor samples. Eligible subjects must have confirmed histologic or cytologic evidence of metastatic or locally advanced solid neoplasm that has failed to respond to standard therapy, progressed despite standard therapy or for which standard therapy does not exist. There is no limit on the number of prior treatment regimens. NCT02003092
1097Background: RX-5902 is a novel oral anti-cancer compound targeting phosphorylated p68 (P-p68)... more 1097Background: RX-5902 is a novel oral anti-cancer compound targeting phosphorylated p68 (P-p68) (RNA helicase DDX5, a member of the DEAD box family of RNA helicases) affecting the Wnt canonical p...
2559Background: RX-0201 is a novel, oligonucleotide that binds native AKT-1 mRNA, preventing down... more 2559Background: RX-0201 is a novel, oligonucleotide that binds native AKT-1 mRNA, preventing downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, to treat metastatic clear cell renal carcinoma. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. Methods: The Phase 1b/2 proof-of-concept, multicenter, open label study is conducted in 2 stages (NCT02089334). Stage 1 is a dose-escalation Phase 1b/2 study of RX-0201 in combination with everolimus (10 mg daily). RX-0201 was given as a continuous intravenous infusion for 14 days followed by 7 days of rest. Subjects were enrolled at increasing doses of RX-0201 in a 3+3 design. The target dose of RX-0201 identified in Stage 1 is being studied further evaluated in Stage 2, which is a randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Plasma concentrations were measured in Stage 1 and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Ver...
4543Background: RX-3117 is an oral small molecule nucleoside analogue (cyclopentyl pyrimidyl nucl... more 4543Background: RX-3117 is an oral small molecule nucleoside analogue (cyclopentyl pyrimidyl nucleoside) that is activated by uridine cytidine kinase 2. RX-3117 shows efficacy in various xenograft ...
Background: BYL719 is an oral inhibitor that selectively targets the a-isoform of class l PI3K. I... more Background: BYL719 is an oral inhibitor that selectively targets the a-isoform of class l PI3K. In a first-inhuman ph1 study in mostly Western patients (pts) with PIK3CA alteration, the maximum tolerated dose for once-daily (qd) BYL719 was declared as 400 mg and preliminary antitumor activity was observed. Previous preliminary findings showed tolerability, safety, and pharmacokinetic (PK) results in dose escalation of the first-in-Japanese ph1 study. Here, we report results of the food effect on the PK profile of BYL719 at steady state, additional safety, and preliminary efficacy in Japanese pts. Methods: Pts were aged 18 years with histologically confirmed, advanced solid tumors. Pts received BYL719 qd in 28-day cycles until disease progression, unacceptable toxicity, or investigator/pts decision. The objectives in the expansion part were to assess food effect on PK profile, preliminary antitumor activity, and safety. Pts with PIK3CA alteration were selected in the expansion part and were randomized to receive BYL719 at the recommended dose 350 mg qd in fasted or fed condition on cycle 1 day 22 and cycle 2 day 1 in a crossover fashion. Pts received BYL719 1 hr following a light breakfast and continued to be fasted for 1 hr after each dose. Results: Thirty-three pts were enrolled and all pts discontinued treatment. The median duration of exposure was 71.0 days (range, 6-462). The common BYL719-related allgrade (Gr) AEs (>30%) were hyperglycemia, rash maculopapular (48.5%, each), diarrhea (45.5%), and decreased appetite (33.3%). BYL719-related Gr 3 or 4 AEs (20%) were rash maculopapular (24.2%) and hyperglycemia (21.2%). Eight pts were enrolled in the expansion part; six of them were eligible for PK analysis. The geometric mean values of dose-normalized C max and AUC 0-24 in fed state were 78% and 56% higher than those in fasted state, respectively. One pt experienced Gr 4-infected neoplasm meeting DLT criteria, 1 pt with uterus cancer and PIK3CA mutation had an unconfirmed partial response, and 18 pts had a stable disease. Conclusions: In this ph1 study of BYL719 in Japanese pts, a positive food effect and preliminary antitumor activity were observed at steady state in pts with PIK3CA mutation status.
Background: RX-0201, a novel, oligonucleotide that binds native AKT-1 mRNA, prevents downstream p... more Background: RX-0201, a novel, oligonucleotide that binds native AKT-1 mRNA, prevents downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth in vitro and is in development for the treatment of metastatic clear cell renal carcinoma Methods: The phase Ib/II proof of concept, multicenter, open label study is conducted in 2 phases. The phase Ib was a dose-escalation study of RX-0201 administered in combination with everolimus. RX-0201 was administered as a continuous intravenous infusion for 14 days followed by 7 days of rest; everolimus was administered at a starting dose of 10mg once daily. Subjects were enrolled at increasing doses of RX-0201 in a modified 3+3 design. Plasma concentrations were measured in phase Ib and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. The dose of RX-0201 identified in phase Ib is being studied further in phase II, which is the randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Results: In the Phase Ib, seven males and 3 females, (median age 61 years) were treated with 125 mg/m⁁2/day (n = 3), 200 mg/m⁁2/day (n = 4), and 250 mg/m⁁2/day (n = 3) RX-0201 in combination with 10 mg everolimus. They received 1-3 lines of therapy prior to study entry (median = 1). The most common toxicities attributed to the combination were rash, mouth ulceration, weight loss, thrombocytopenia, facial edema, fatigue, and pruritus. No significant events were attributed to RX-0201 alone. Most events (81%) were mild or moderate in severity. Based on the tolerability, 250 mg/m⁁2/day RX-0201 dose was declared the recommended phase II dose. Three subjects in the phase Ib have experienced stable disease for 383, 191, and 122 days; a tumor burden reduction of 16 and 36% was seen in 2 subjects. RX-0201 PK demonstrated a dose proportional exposure. Conclusions: RX-0201, in combination with everolimus, appears to be safe and well tolerated in patients with metastatic renal cancer at doses up to 250 mg/m⁁2/day. Randomized phase II of this trial is currently ongoing. Citation Format: Scott Tagawa, Gurkamal S. Chatta, Sumanta K. Pal, Sanjay Goel, Reza Mazhari, Callie Heaton, Ely Benaim, Neeraj Agarwal. Phase Ib/II Study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma - Phase Ib results. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT114.
646 Background: RX-0201 is a novel 20-mer oligonucleotide that binds to mRNA coding for AKT-1, pr... more 646 Background: RX-0201 is a novel 20-mer oligonucleotide that binds to mRNA coding for AKT-1, preventing AKT-1 expression and limiting the amount of downstream p-AKT. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. RX-0201, in combination with everolimus, to treat mRCC was evaluated in a Phase 1b/2 clinical study. Methods: This Phase 1b/2 study (2‐stage design, NCT02089334 ) evaluated the efficacy and safety of RX‐0201 in combination with everolimus in eligible subjects with mRCC. Eligible subjects must have had confirmed histologic or cytologic evidence of renal cancer with a clear cell component, measurable disease as defined by RECIST, received at least 1 course of therapy with a VEGFR inhibitor and progressed within 6 months of planned first dose of on study treatment. In Phase 1 subjects were enrolled at increasing doses of RX-0201 (delivered via continuous IV for 14 days) in combination with 10 mg/day everolimus in a modified 3+3 design. The target dose of RX-0201 identified in Phase 1, 250 mg/m2/day, was further evaluated in Phase 2. Primary objectives included the safety and efficacy at the recommended Phase 2 dose. The Phase 2 primary endpoint was progression free survival (PFS) benefit for at least 4.5 months. Results: Eleven subjects (7 males, 4 females) with mRCC were treated with RX-0201 (250 mg/m2/day) + everolimus (10 mg/ day) in Phase 2. The median age was 63 years, ECOG performance status at screening was 0 to 1, and 55% received ≥ 3 prior therapies. The median PFS in evaluable subjects was 4.9 months. Four subjects had stable disease after 6 months of treatment. The most frequent related adverse events ( > 15%) were G1/2 epistaxis, G3 fatigue, G1/2 nausea and G1 vomiting. Conclusions: In this mRCC population with extensive prior therapy, RX‐0201 in combination with everolimus was safe, well-tolerated, and showed promising efficacy. The results also support the therapeutic significance of the AKT-1/mTOR pathway in mRCC. Clinical trial information: NCT02089334.
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2014
Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported i... more Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/ day once-daily (QD) for 14 days plus 14 days' rest, all in 28day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21day cycles. Results Fifty-eight patients were enrolled (PIC n = 28, ECT n =30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma. Keywords Phase I-III Leukemia and lymphomas. Novel antitumor agent. Cell cycle mechanisms of anticancer drug action. Aurora A kinase inhibitor. MLN8237 ClinicalTrials.gov identifier: NCT00697346 Electronic supplementary material The online version of this article
Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside th... more Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 2 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 2 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% of evaluable subjects with a partial response rate or better. Results: As of Sep 2017, 44 subjects have been enrolled (22 females, 22 males). The median age was 68 years, ECOG performance statuses were 0 (13 subjects) and 1 (31 subjects) and 6 subjects had received 4 or more prior therapies. One subject had an unconfirmed partial response and 21 subjects met the primary endpoint of stable disease with a duration of 30-224 days. The most frequent adverse events were mild to moderate anemia (19%), mild to moderate fatigue (15%), mild to moderate diarrhea (11%), and severe anemia (9%). Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. The study continues to enroll subjects with advanced pancreatic cancer into stage 2. A phase 2 study with nab-paclitaxel in first-line patients with advanced pancreatic cancer has been started.
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