A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

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Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination with Bortezomib in Patients with Advanced Multiple Myeloma.

Blood ◽

10.1182/blood.v110.11.1172.1172 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1172-1172 ◽

Cited By ~ 14

Author(s):

Donna M. Weber ◽

Sundar Jagannath ◽

Amitabha Mazumder ◽

Ronald Sobecks ◽

Gary J. Schiller ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Phase I ◽

Stable Disease ◽

Phase I Trial ◽

Performance Status ◽

Single Agent ◽

Primary Objective ◽

Combination Regimen ◽

Ecog Performance Status

Abstract Background: Vorinostat is a histone deacetylase inhibitor that has demonstrated antiproliferative and proapoptotic activity alone and in combination with the proteasome inhibitor bortezomib in preclinical multiple myeloma (MM) models. In a Phase I study, vorinostat also demonstrated modest single agent activity in patients (pts) with relapsed or refractory MM. Patients and Methods: We conducted a Phase I trial of oral vorinostat (200 mg bid or 400 mg daily × 14 days (d1–14) in combination with bortezomib 0.7 or 0.9 mg/m2 i.v. on d 4, 8, 11 and 15 or 0.9, 1.1, or 1.3 mg/m2 i.v. on d 1, 4, 8 and 11. Cycles were repeated every 21 d for a maximum of 8 cycles until progressive disease (PD) or intolerable toxicity. Pts with active relapsed or refractory MM who had not received bortezomib in the preceding 3 months and with adequate hematologic, hepatic, and renal function, and ECOG performance status of 0–2 were eligible. The primary objective was to determine the maximum tolerated dose (MTD). Activity (utilizing EBMT criteria) and safety of the combination regimen were also assessed. Results: Twenty pts have been enrolled: median age, 61 years (range 52–76), median number prior systemic therapies, 3 (range 1–14), prior therapy with bortezomib (4 pts). Eighteen pts have received ≥ 1 dose and were evaluable for safety as of 7/1/07. One pt (cohort 3) experienced a dose-limiting toxicity (DLT, Table). The MTD has not been reached. The most common drug-related toxicities of any grade were nausea (56%), thrombocytopenia (50%), diarrhea (39%), vomiting (39%), fatigue (39%), and anemia (22%). Grade ≥ 3 drug-related adverse events were thrombocytopenia (33%, none associated with bleeding), peripheral neuropathy (11%), neutropenia (11%, none associated with fever), diarrhea (6%), diverticulitis (6%), fatigue (6%), increased AST (6%), memory changes (6%), nausea (6%), vomiting (6%), and upper respiratory infection (6%). Eight pts discontinued treatment, 3 due to PD and 5 due to adverse experiences [fatigue (2), nausea (2), diverticulitis (1)]. Of 17 evaluable pts for efficacy, all had measurable response or stable disease; 4 had a partial response, 2 had a minimal response, and 11 stable disease. Among 3 evaluable pts previously treated with bortezomib, 1 achieved a partial response and 1, minimal response. Pts at the highest dose level were not yet evaluable for response. Conclusion: Although accrual continues to determine the MTD, the combination of vorinostat and bortezomib is well tolerated and effective in this group of heavily pretreated pts with refractory/relapsed MM. Table Cohort Vorinostat Dose (mg) Bortezomib Dose (mg/m2) N # of Cycles DLTs Best Response MR = minimal response; NE = not evaluable; PR = partial response; SD = stable disease. *Days 4, 8, 11 and 15. †Days 1, 4, 8 and 11. ‡Treatment cycle in progress. 1 200 0.7* 3 3, 3, 14 - SD (2), PR 2 200 0.9* 3 4, 5, 6 - SD (2), PR 3 400 0.9† 6 2, 3, 5, 6, 6, 6 Transient AST elevation SD (3), MR, PR (2) 4 400 1.1† 5 3, 3, 4, 5, 11 - SD (4), MR 5 400 1.3† 3 1‡, 1‡, 2 - NE (3)

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344 Avelumab + binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC): dose-escalation results from the phase 1b/2 JAVELIN PARP MEKi trial

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.344 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A371-A371

Author(s):

Jordi Rodon ◽

Daniel Weng Tan ◽

Ignacio Garrido Laguna ◽

Wael Harb ◽

J Thaddeus Beck ◽

...

Keyword(s):

Partial Response ◽

Stable Disease ◽

Creatine Phosphokinase ◽

Retinal Pigment ◽

Single Agent ◽

Objective Response ◽

Ductal Adenocarcinoma ◽

Mucosal Inflammation ◽

Number Of Patients ◽

Phase 1B

BackgroundPreclinical studies of avelumab (anti–PD-L1) + binimetinib (MEK inhibitor [MEKi]) showed encouraging antitumor activity. We report results from the phase 1b JAVELIN PARP MEKi trial (NCT03637491) evaluating avelumab + binimetinib in patients with mPDAC.MethodsEligible patients had mPDAC and disease progression during or following 1–2 prior lines for advanced or metastatic disease. Patients received avelumab 800 mg intravenously every 2 weeks and binimetinib 30 or 45 mg orally twice daily. The primary endpoint for phase 1b was dose-limiting toxicity (DLT). Secondary endpoints included safety, confirmed objective response per investigator (RECIST 1.1), pharmacokinetics, immunogenicity, and biomarker analyses. PD-L1 expression (SP263 assay) and CD8+ tumor-infiltrating lymphocytes (TILs) in baseline tumor samples were assessed using immunohistochemistry. Molecular alterations were assessed via plasma ctDNA analyses. Blood samples were collected to assess trough concentrations for avelumab, binimetinib, and AR00426032 (binimetinib metabolite) and end-of-infusion concentration for avelumab.Results22 patients received avelumab + binimetinib 30 mg (n=10) or 45 mg (n=12); all discontinued treatment. Among 21 DLT-evaluable patients, DLTs occurred in 3/10 (30.0%) in the 30-mg group (mucosal inflammation, dermatitis acneiform, blood creatine phosphokinase increased [n=1 each]) and 5/11 (45.5%) in the 45-mg group (detachment of retinal pigment epithelium, abdominal pain, diarrhea, nausea, vomiting, rash pustular, hypertension, blood creatine phosphokinase increased [n=1 each]). Any-grade treatment-related adverse events (TRAEs) occurred in all 22 patients; grade =3 TRAEs occurred in 8 (80.0%) and 4 (33.3%) in the 30- and 45-mg groups, respectively, most commonly blood creatine phosphokinase increased (n=3 [30.0%], n=2 [16.7%], respectively). No treatment-related deaths occurred. Objective response rates (95% CI) in the 30- and 45-mg groups were 0% (0.0–30.8) and 8.3% (0.2–38.5; 1 partial response), respectively; 1 (10.0%) and 6 (50.0%) had a best overall response of stable disease. Tumor shrinkage was associated with higher baseline PD-L1 expression, higher number of CD8+ TILs, and MEK1/2, PIK3CA, and RNF43 alterations, whereas ERBB4 alterations correlated inversely with tumor size change. Available data indicate that avelumab, binimetinib, and AR00426032 exposures were within range of previous monotherapy studies.ConclusionsThis study was terminated before a recommended phase 2 dose was established. In patients with mPDAC who received avelumab + binimetinib, DLTs occurred in both dose groups, although TRAEs were generally consistent with single agent safety profiles. The 45-mg binimetinib dose had a higher number of patients with stable disease and one confirmed partial response. Biomarker findings provide insights into potential mechanisms of treatment resistance and response.Trial RegistrationNCT03637491Ethics ApprovalThe trial was approved by each site’s independent ethics committee.

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Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001752 ◽

2021 ◽

Vol 9 (4) ◽

pp. e001752

Author(s):

Rivka R Colen ◽

Christian Rolfo ◽

Murat Ak ◽

Mira Ayoub ◽

Sara Ahmed ◽

...

Keyword(s):

Partial Response ◽

Stable Disease ◽

Progressive Disease ◽

Tumor Response ◽

Complete Response ◽

Classification Model ◽

P Value ◽

Rare Cancer ◽

Rare Cancers ◽

Contrast Enhanced Ct

BackgroundWe present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers.MethodsThe study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 “controlled disease” (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance.FindingsThe 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively.ConclusionOur radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.InterpretationOur radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.

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ANCHOR (OP-104): Melflufen plus dexamethasone (dex) and bortezomib (BTZ) in relapsed/refractory multiple myeloma (RRMM)—Optimal dose, updated efficacy and safety results.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8037 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8037-8037

Author(s):

Roman Hajek ◽

Luděk Pour ◽

Miquel Granell ◽

Vladimir Maisnar ◽

Paul G. Richardson ◽

...

Keyword(s):

Partial Response ◽

Cardiac Failure ◽

Alkylating Agents ◽

Phase 1 ◽

Optimal Dose ◽

Complete Response ◽

Primary Objective ◽

Clinical Activity ◽

Development Of Resistance ◽

Grade 3

8037 Background: Development of resistance to standard treatments for RRMM highlights the need for novel therapies. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen + dex showed clinical activity and an acceptable safety profile in HORIZON (Richardson et al. J Clin Oncol. 2020 Dec 9 [Epub]). This is an update of the BTZ arm of the phase 1/2a ANCHOR study (NCT03481556). Methods: Patients (pts) with RRMM were intolerant or refractory to a prior IMiD, with 1-4 prior lines of therapy (LoTs). Prior treatment with a proteasome inhibitor (PI) was allowed, but pts could not be refractory to PIs in the last LoT. Melflufen (30, 40, or 20 mg intravenously; d 1 of each 28-d cycle) was administered with BTZ (1.3 mg/m2 subcutaneous) + oral dex (20 mg on d 1, 4, 8, and 11 and 40 mg on d 15 and 22; dex dose reduced if aged ≥ 75 y). The primary objective in phase 1 was to determine the optimal phase 2 dose of melflufen for this combination. Results: As of the data cutoff date (October 19, 2020), 13 pts received melflufen (30 mg, n = 6; 40 mg, n = 7) + dex and BTZ. In the 30 mg and 40 mg cohorts, respectively, median age was 78.5 y (range, 70-82) and 70.0 y (range, 61-76); median prior LoTs was 3.5 (range, 2-4) and 2.0 (range, 1-4); 33% and 50% of evaluable pts had high-risk cytogenetics; 83% and 71% were refractory to last LoT; 100% and 86% received a prior PI; 33% and 14% were refractory to PIs. In the 30 mg and 40 mg cohorts, respectively, median treatment duration was 6.5 mo (range, 1.4-29.0) and 8.7 mo (range, 2.1-19.6); 4 (67%) and 4 pts (57%) were still on treatment; 2 and 3 pts discontinued (30 mg: progressive disease [PD] and other [1 pt each]; 40 mg: adverse event [AE], lack of efficacy, and PD [1 pt each]). Confirmed overall response rate in the 30 mg and 40 mg cohorts, respectively, was 50% (1 very good partial response [VGPR] and 2 partial response [PR]) and 71% (1 complete response, 3 VGPR, and 1 PR). Most common grade 3/4 treatment-related AEs (TRAEs) were thrombocytopenia (30 mg: 50%; 40 mg: 100%) and neutropenia (30 mg: 33%; 40 mg: 71%); grade 3/4 nonhematologic TRAEs were infrequent; 3 pts discontinued study treatment due to treatment-emergent AEs (30 mg: cardiac failure chronic and osteolysis [1 pt each]; 40 mg: thrombocytopenia [1 pt]). Serious TRAEs occurred in 2 pts (33%) in the 30 mg cohort (neutropenia and pneumonia [1 pt], syncope [1 pt]) and 1 pt (14%) in the 40 mg cohort (thrombocytopenia and neutropenia). No dose-limiting toxicities occurred at either dose level. Fatal AEs occurred in 1 pt in the 30 mg cohort (cardiac failure chronic; unrelated to study treatment). Conclusions: ANCHOR determined that the optimal dose of melflufen is 30 mg + dex and BTZ; results showed clinical activity in heavily pretreated pts. Recruitment is ongoing; updated data will be presented. Clinical trial information: NCT03481556.

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Calcium Electroporation of Equine Sarcoids

Animals ◽

10.3390/ani10030517 ◽

2020 ◽

Vol 10 (3) ◽

pp. 517

Author(s):

Stine K. Frandsen ◽

Julie Gehl ◽

Trine Tramm ◽

Martin S. Thoefner

Keyword(s):

Partial Response ◽

Treatment Efficacy ◽

Treatment Options ◽

Complete Response ◽

Total Response ◽

High Calcium ◽

Anti Cancer ◽

Location Type ◽

Term Response

Sarcoids are common equine skin tumors where the risk of recurrence after treatment is high, and better treatment options are warranted. Calcium electroporation is a novel anti-cancer treatment where lethally high calcium concentrations are introduced into the cells by electroporation, a method where short high-voltage pulses induce transient permeabilization of the cell membrane. This study investigated the safety and long-term response of calcium electroporation on sarcoids. Thirty-two sarcoids in eight horses were included. The study suggested that calcium electroporation is a safe and feasible treatment for sarcoids, including inoperable sarcoids. Horses were treated once (2/8) or twice (6/8) under general anesthesia, where sarcoids were injected with 220 mM calcium chloride followed by electroporation with 8 pulses of 100 μs, 1 kV/cm, and 1 Hz. Biopsies were taken prior to treatment. The sarcoid size was monitored for 12–38 weeks after the first treatment. Complete response was observed in 22% (6/27) of treated sarcoids, and partial response in 22% (6/27), giving a 44% total response. Treatment efficacy did not appear to be related to location, type, or size. In all non-biopsied lesions, a complete response was seen (4/4). In conclusion, in this small study, 44% of sarcoids responded with 22% of sarcoids disappearing.

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Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group

Journal of Clinical Oncology ◽

10.1200/jco.2010.34.1578 ◽

2011 ◽

Vol 29 (24) ◽

pp. 3278-3285 ◽

Cited By ~ 226

Author(s):

Amit M. Oza ◽

Laurie Elit ◽

Ming-Sound Tsao ◽

Suzanne Kamel-Reid ◽

Jim Biagi ◽

...

Keyword(s):

Endometrial Cancer ◽

Partial Response ◽

Phase Ii ◽

Median Duration ◽

Stable Disease ◽

Mutational Analysis ◽

Single Agent ◽

Protein Translation ◽

Mtor Inhibition ◽

Phase Ii Studies

Purpose Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. Patients and Methods Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. Results In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. Conclusion mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.

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A Multicenter, Single-Arm, Open-Label Study To Evaluate the Efficacy and Safety of Single-Agent Lenalidomide in Patients with Relapsed and Refractory Multiple Myeloma; Prelininary Results.

Blood ◽

10.1182/blood.v106.11.1565.1565 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1565-1565 ◽

Cited By ~ 13

Author(s):

Paul Richardson ◽

Sundar Jagannath ◽

Mohamad Hussein ◽

James Berenson ◽

Seema Singhal ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Stable Disease ◽

Single Agent ◽

Phase 2 ◽

Open Label ◽

Open Label Study ◽

Label Study ◽

Multicenter Phase ◽

Best Response

Abstract INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory MM determined that the maximum tolerated dose (MTD) of lenalidomide was 25 mg/day, based upon myelosuppression encountered beyond 28 days, which was manageable with growth factor support and dose reduction. In a multicenter phase 2 study to determine optimal dose and schedule, 102 pts with relapsed or refractory MM were randomized to receive lenalidomide at either 15 mg bid (n=34) or 30 mg qd (n=68), for 21 days every 4 wks. Both treatment arms showed significant activity with manageable toxicity. An increased incidence of cytopenia was noted in the 15-mg bid group and thus the 30 mg qd schedule was taken forward. METHODS: The objective of this multicenter, phase 2, open-label study (CC-5013-MM-014) was to further evaluate the effectiveness and safety of single-agent lenalidomide administered at a dose of 30 mg qd for 21 days every 28 days (28-day cycle) in pts with relapsed and refractory MM. Eligible patients included those who had received prior thalidomide, bortezomib, or SCT. RESULTS: 222 pts were enrolled into the study. All patients had received at least 2 prior anti-myeloma treatments, including bortezomib (41%), thalidomide (80%), and SCT (44%). Table 1 shows Best Response data, excluding patients in whom responses were not evaluable (n=10). Partial response or better occurred in 25% of patients and SD or better in 71%. Time to Progression was a median of 22.4 wks (range 1.8– 66 wks). The median survival has not been reached (the lower bound of the 95% CI exceeds 15 months). The most common treatment-related AEs (those reported in ≥10% of patients overall) included upper respiratory tract infection, neutropenia and thrombocytopenia. AEs that most frequently led to dose reduction or interruption by percentage of cases were neutropenia (40%), thrombocytopenia (23%), fatigue (5%), and anemia (5%). CONCLUSION: Oral lenalidomide in relapsed and refractory MM patients achieved PR+CR in 25%, stable disease or better in 71%, a median TTP of approximately 6 months and a median survival that has not been reached. Toxicity has been manageable with a very low incidence of DVT and minimal treatment-emergent neuropathy. Table 1. Best Response Best Response* n (%) *Excluding patients not evaluable (n=10); CR=complete response and PR=partial response (EBMT criteria) ≥PR (CR + PR) 53 (25) Stable disease 152 (71)

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Single Agent Tamibarotene Has Activity in Acute Promyelocytic Leukemia Patients Previously Treated with ATRA and Arsenic Trioxide, but Does Not Produce Durable Responses

Blood ◽

10.1182/blood.v124.21.3751.3751 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3751-3751 ◽

Cited By ~ 1

Author(s):

David Sanford ◽

Francesco LoCoco ◽

Miguel A. Sanz ◽

Eros Di Bona ◽

Steven Coutre ◽

...

Keyword(s):

Retinoic Acid ◽

Complete Remission ◽

Partial Response ◽

Adverse Events ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Single Agent ◽

Complete Response ◽

Promyelocytic Leukemia ◽

Cell Transplant

Abstract Background: Treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is highly effective as first-line therapy, although approximately 10% of patients relapse after treatment. Several mechanisms of ATRA resistance have been proposed including accelerated clearance of ATRA and increased levels of cellular retinoic acid-binding protein (CRABP), which induces retinoic acid metabolism. Tamibarotene is a synthetic retinoid that does not significantly bind CRABP, suggesting that it might be effective in APL patients with ATRA resistance. Tamibarotene has shown efficacy in APL patients with relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA Methods: We conducted a multicenter phase II clinical trial of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO (concomitant or sequential). Participants were treated with single agent tamibarotene at a daily dose of 6 mg/m2 for up to 56 days during induction. Patients achieving a complete response were eligible to continue on consolidation treatment with tamibarotene at the same dose for a maximum of six 28 day cycles. The primary outcome for this trial was to determine the rate of durable complete response (CR) using tamibarotene as a single agent. Secondary outcomes included the rate of morphologic complete remission, partial response, cytogenetic complete response, molecular complete response as well as the safety profile and tolerability of this medication. Results: We enrolled 14 patients from March 2008 to October 2011 at 8 centers. The median age of the participants was 56 years (range 20-76). Twelve patients had relapsed APL and 2 had primary refractory disease. Patients had a median of 2 remissions (range 1-5) prior to enrollment with a median time from the most recent remission to study screening of 23 months (range 2-102). Twelve patients (86%) had received other treatments including stem cell transplant (n=4) in addition to ATO and ATRA prior to enrollment. Eight patients achieved a morphologic remission during treatment with tamibarotene and 2 had a partial response (>50% reduction in BM blasts). Three (21%) patients with complete morphologic remission had a CR, whereas 5 (36%) had a complete remission with incomplete hematologic recovery (CRi), without meeting pre-specified recovery of neutrophil (>1,000/μL) and platelet counts (>100,000/μL). Seven out of 8 patients who achieved CR or CRi relapsed after treatment. The median duration of response for patients achieving CR was 203 days (range 183-212). The median overall survival for the entire group was 233 days (95% CI 196-526 days). Thirteen patients reported treatment-emergent adverse events, although the majority were mild (Grade 1-2). The most frequently reported adverse events included rash (n=6, grade 1-3), headache (n=4, grade 1) and neutropenia (n=3, grade 3-4). Two patients experienced APL differentiation syndrome (grade 2). Two patients discontinued the study due to adverse events: one patient developed progressive multifocal leukoencephalopathy and the other developed pneumonia, although neither of these events was thought to be related to tamibarotene. Discussion: These results suggest that tamibarotene has activity in patients with relapsed APL after treatment with ATO and ATRA. Although the CR rate of 21% is lower than that reported in a previous trial using tamibarotene (58%; Tobita, 1997), the 24 patients in that study had received ATRA alone or in combination with chemotherapy, but not ATO. Thus, tamibarotene has significant clinical activity in this heavily pre-treated population with acceptable toxicity. Further studies using tamibarotene as initial therapy and in combination with ATO are warranted. Disclosures LoCoco: Lundbeck: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau. Cortes:CytRx: Research Funding.

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A Phase I/II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v124.21.3252.3252 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3252-3252 ◽

Cited By ~ 3

Author(s):

Shyamala C. Navada ◽

Guillermo Garcia-Manero ◽

Francois Wilhelm ◽

Katherine Hearn ◽

Rosalie Odchimar-Reissig ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Stable Disease ◽

Blood Count ◽

Single Agent ◽

Complete Response ◽

Leukemic Cells ◽

Cell Transplant ◽

Transfusion Requirements ◽

Count Recovery

Abstract Background:Rigosertib is a small molecule anti-cancer agent targeting PI3/polo-like kinase pathways that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent with the intravenous (IV) formulation in patients (pts) who have relapsed or are refractory to hypomethylating agents (HMAs) as well as with the oral formulation in lower-risk, red-cell transfusion-dependent MDS patients. Azacitidine (AZA) is first-line therapy for pts with higher-risk MDS. In vitro, the combination of rigosertib with AZA acts synergistically to inhibit growth and induce apoptosis of leukemic cells (Skidan et al 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. These nonclinical results provided the rationale to combine the 2 agents in a phase I/II study in pts with MDS and AML. Methods: Pts with MDS and non-proliferative AML, who were previously untreated or had failed or progressed on an HMA were included in the phase I component of the study. Oral rigosertib was administered twice daily from day 1 through day 21 of a 28-d cycle. AZA 75 mg/m2/d was administered for 7 days starting on day 8 of the 28-d cycle. Pts were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg twice daily; [2] 280 mg twice daily; [3] 560 mg qAM and 280 mg qPM. A CBC was performed weekly and a bone marrow (BM) aspirate and/or biopsy was performed at baseline and every 4-8 weeks afterwards. Results: Eighteen pts have been treated with the combination of oral rigosertib and AZA. Pts had diagnoses of intermediate-1 MDS (3), intermediate-2 MDS (6), high-risk MDS (2), CMML (1), and AML (6); median age was 70.5 years; 61% of pts were male. Pts have received 1-10+ cycles of treatment with the total number of cycles administered thus far being 58. Cytogenetic profiles by IPSS were good (8 pts), poor (8 pts), and intermediate (2 pts). 11of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. One patient became RBC transfusion independent after 3 cycles of treatment. 5 additional patients have had a reduction in their RBC and platelet transfusion requirements. 56% of patients received prior treatment with HMAs: AZA (6 pts), decitabine (4 pts). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Elevation in creatinine in 1 pt in cohort 1 was a possibly related grade 3 dose-limiting toxicity that required subsequent expansion of the cohort. Drug-related dysuria/cystitis was not reported in this pt population. Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: Complete Response (CR) (1 pt), Cri (CR with incomplete blood count recovery) (4 pts), stable disease (2), hematologic improvement-erythroid (1). Six pts received fewer than 4 cycles of treatment and are too early to evaluate. Six pts came off study for the following reasons: progression of disease (1), pt request (1), death from pneumonia (2), received stem cell transplant (1), persistent fungal pneumonia (1). Two evaluable pts have responded to the combination after progression or failure on HMA alone. Conclusions: The combination oforalrigosertib at 560/280 mg BID (recommended phase II dose) and standard-dose AZA can be safely administered and appears to be well tolerated in repetitive cycles in pts with MDS and non-proliferative AML. The AE profile does not differ significantly from that of AZA alone. Data from the Phase I component of this study suggest activity in patients with MDS after HMA failure. Additional data are required to evaluate this observation. The Phase II segment of this study is underway to further assess the response of the combination. Table Patient ID Diagnosis Prior HMA % Blasts in BM at Baseline % Blasts in BM after Treatment IWG Response 1 MDS No 2 1 CRi 2 AML No 40 0 CRi 3 AML No 22 N/A NE 4 MDS Azacitidine 0 0 NE 5 AML No 59 N/A NE 6 MDS No 21 <5 CRi 7 MDS No 2 1 CR 8 MDS No 2.5 2 SD 9 AML Decitabine 25 N/A NE 10 MDS Decitabine 12 3 CRi 11 CMML Azacitidine 2 3 SD 12 MDS Azacitidine 4 1 HI-E 13 AML Azacitidine 47 40 TE 14 AML Decitabine 7 7 TE 15 MDS No 9 5 TE 16 AML No 25 6 TE 17 AML No 15 19 TE 18 AML Azacitidine 64 45 TE IWG = International Working Group CR = Complete Response CRi = Complete Response with incomplete blood count recovery NE = Not Evaluable SD = Stable Disease HI-E = Hematologic Improvement - Erythroid TE = Too Early Disclosures Wilhelm: Onconova Therapeutics, Inc: Employment, Equity Ownership. Demakos:Onconova: Consultancy. Azarnia:Onconova Therapeutics, Inc: Employment. Silverman:Onconova: with Icahn School of Medicine at Mount Sinai Patents & Royalties.

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Safety and efficacy of the BCL2 inhibitor venetoclax in estrogen receptor (ER) and BCL2-positive metastatic breast cancer: The mBEP study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1044 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1044-1044 ◽

Cited By ~ 4

Author(s):

Geoffrey John Lindeman ◽

Sheau Wen Lok ◽

Alice Ruth Bergin ◽

James Richard Whittle ◽

Kylie Shackleton ◽

...

Keyword(s):

Breast Cancer ◽

Partial Response ◽

Stable Disease ◽

Tumor Regression ◽

Metastatic Breast ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Common Adverse Event ◽

Royal Melbourne Hospital ◽

Safety And Efficacy

1044 Background: The anti-apoptotic protein BCL2 is overexpressed in ~85% of ER+ breast cancer (BC). Venetoclax (ABT-199), a BCL2 inhibitor approved for CLL (400 mg/day), synergizes with tamoxifen in preclinical patient derived xenograft models by increasing apoptosis. In the first study to evaluate venetoclax in solid tumors, we tested the safety and efficacy of this combination in ER+BCL2+ metastatic BC. Methods: A ‘3+3 design’ dose escalation phase 1b study enrolled women with ER+ ( > 1%), BCL2+ ( > 10%, mod-high) and HER2 non-amplified metastatic BC. Patients received escalating doses of venetoclax 200, 400, 600 or 800 mg/day with tamoxifen 20 mg/day. The primary objective was to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) over 4 weeks. There was no limit to the number of prior lines of therapy. Results: Fifteen patients were enrolled (mean age 62 years, range 44-78; previous tamoxifen, 10 pts). Mean lines of prior therapy for metastatic BC was 2.5 (median 2, range 0-6) and included tamoxifen (6 pts). ESR1 mutations were present in ctDNA of 4 patients. Treatment was well tolerated, with no DLT observed. MTD was not reached; 6 patients received the maximal planned dose (800 mg). The most common adverse event (AE) was lymphopenia (67% Grade 1-2; 13% Grade 3; No Grade 4), followed by nausea (46%, Grade 1-2), which was readily managed. Of 13 women with measurable disease (RECIST v1.1), 4 (31%) had a partial response and 5 (38%) had stable disease (clinical benefit rate, 69%). For patients with a partial response, tumor regression was rapid (evident at first restaging) and occurred in the 400-800 mg dose levels. Two patients with non-measurable bone-only disease had clinically stable disease (1 ongoing > 64 weeks). The median duration of response has not yet been reached (range, 12 to > 64 weeks). Conclusions: We demonstrated the safety of tamoxifen and venetoclax in ER+BCL2+ metastatic BC, with preliminary evidence of clinically relevant activity. A dose expansion study including serial biopsy, ctDNA and PET scans is ongoing at the 800 mg/day recommended phase 2 dose. Sponsor: Royal Melbourne Hospital Clinical trial information: ISRCTN98335443 , ACTRN12615000702516.

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