Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4503-4503 ◽  
Author(s):  
David C. Smith ◽  
Thomas Gajewski ◽  
Omid Hamid ◽  
Jeffrey S. Wasser ◽  
Anthony J. Olszanski ◽  
...  
Keyword(s):  
Phase I ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Advanced Disease ◽  
Alternative Therapy ◽  
Phase Iii ◽  
Open Label ◽  
Advanced Urothelial Carcinoma ◽  
Grade 3 ◽  
Line Of Therapy

4503 Background: Pembrolizumab (P), a PD-1 inhibitor, is active and well tolerated in platinum-treated, advanced urothelial carcinoma (UC). Epacadostat (E) potently and selectively inhibits indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study of E + P in pts with advanced tumors. We report phase I/II efficacy and safety outcomes for the UC cohort at an October 29, 2016 data cutoff. Methods: Adult pts with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate), and no prior checkpoint inhibitor therapy were eligible to participate. In phase I, pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1–evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: A total of 40 pts (phase I, n = 5; phase II, n = 35) were evaluated. Median age was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease. Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable pts were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). PFS and biomarker analyses are ongoing. The most common TRAEs (≥10% of 40 pts) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of pts (rash was the only grade ≥3 TRAE to occur in > 1 pt [n = 3]). Three pts discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). Conclusions: E + P was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in pts with advanced UC. A phase III UC study is planned. Clinical trial information: NCT02178722.

Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

2003 ◽  
Vol 21 (15) ◽  
pp. 2926-2932 ◽  
Author(s):  
David H. Ilson ◽  
Manjit Bains ◽  
David P. Kelsen ◽  
Eileen O’Reilly ◽  
Martin Karpeh ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Concurrent Radiotherapy ◽  
Minimal Toxicity ◽  
Grade 3

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

Tolerability and Efficacy of Bortezomib Added to CVP-R for Previously Untreated Advanced Stage Follicular Lymphoma: Interim Analysis of a Phase II Study by the NCIC Clinical Trials Group.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1576-1576 ◽  
Author(s):  
Laurie H Sehn ◽  
David A Macdonald ◽  
Sheldon H. Rubin ◽  
Morel Rubinger ◽  
Kevin R Imrie ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Interim Analysis ◽  
Standard Dose ◽  
Single Agent ◽  
Acceptable Level ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Grade 3

Abstract Background: Despite recent improvements in therapy, follicular lymphoma (FL) remains incurable with standard treatment, warranting investigation of new approaches. Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with FL. This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R). Methods: This is a phase II multi-center open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose C(750 mg/m2) V(1.4 mg/m2, capped at 2 mg) P(40 mg/m2 × 5) –R(375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Planned accrual is 90 patients. A two-stage design was employed with a planned interim analysis of the first 28 patients to ensure an acceptable level of neurotoxicity (defined as less than 5/28 patients with grade 3/4 neurotoxicity after the first 4 cycles) and meaningful response rate (more than 12/28 patients with a complete response following 8 cycles), prior to enrolling remaining patients. Results: Median age of the first 28 patients was 55 years (range, 30–73). Fifty percent were male and 79% had stage IV disease. FLIPI score at study entry: low 14%, intermediate 43%, high 43%. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. To date, no pts have developed grade 4 neurotoxicity and only 1/28 (4%) has developed grade 3 neurotoxicity within the first 4 cycles (neuropathic pain which resolved without need for treatment modification). The incidence of grade 1 and 2 neurotoxicity was 54% and 25% respectively. Only 3 pts discontinued therapy prematurely (2 pt refusal, 1 progressive disease). Ninety-four percent of planned bortezomib treatments in the first four cycles and 93% of vincristine doses were administered without dose reduction. Hematologic toxicity was mild, with no pts experiencing grade 3/4 anemia or thrombocytopenia. Only 2 episodes of febrile neutropenia occurred and no grade 3/4 infections were noted. Although it is too early to report on efficacy in this ongoing trial, response objectives for stage I have been met, and enrollment to stage 2 is underway. Conclusions: The addition of bortezomib to standard dose CVP-R is very well tolerated, with an acceptable level of neurotoxicity, without compromising the delivery of bortezomib or vincristine. This ongoing study will provide toxicity and efficacy data to facilitate the development of a planned phase III trial.

Activity and safety of Nab-FOLFIRI and Nab-FOLFOX as first-line treatment for metastatic pancreatic cancer (phase II NabucCO study).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 351-351 ◽  
Author(s):  
Elisa Giommoni ◽  
Evaristo Maiello ◽  
Vanja Vaccaro ◽  
Ermanno Rondini ◽  
Caterina Vivaldi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
First Line ◽  
Open Label ◽  
Grade 3

351 Background: FOLFIRINOX is an approved regimen for metastatic pancreatic cancer (mPC). We performed a modification in FOLFIRINOX schedule, using nab-paclitaxel (nab-p) to obtain two regimens that could be as effective and less toxic than the original triplet. NabucCO study was a randomized phase II trial to assess activity and toxicity of nab-p instead of either oxaliplatin (Nab-FOLFIRI) or irinotecan (Nab-FOLFOX) in first line setting. Previous dose–finding NabucCO study defined that maximum tolerated dose of nab-p with FOLFIRI is 120 mg/m2, and with FOLFOX is 160 mg/m2. Methods: The study was a 1:1 parallel arm, open label, not comparative one to assess overall response rate (ORR) of Nab-FOLFIRI and Nab-FOLFOX as primary end-point. Patients (pts) with PS 0-1, untreated for mPC were randomized to receive leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2, irinotecan 180 mg/m2 plus nab-p 120 mg/m2 (arm A) or leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2 and oxaliplatin 85 mg/m2 iv plus nab-p 160 mg/m2 (arm B) every 2 weeks for up to 12 cycles. Secondary end points were clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), and safety. Results: From November 2015 to January 2017, 84 pts were treated (42 for each arm). Median age was 60 years (29-65) in arm A and 64 years (47-64) in arm B. The ORR was 31 % for both schedules, with a CBR of 69% and 71%, respectively. At a median follow-up of 11.4 months for arm A and 14.5 months for arm B (censored on august, 31th 2017), 1-year survival is 41% and 50%, respectively. For Nab-FOLFIRI PFS and mOS were 6 months (90% CI: 4.9-8.0) and 13.2 months (90% CI: 8.3-14.8), while in Nab-FOLFOX were 5.6 months (90% CI:4.9-7.2) and 10.8 months (90% CI: 8.4-12.8). Grade ≥3 toxicities in arm A were neutropenia (19%) and febrile neutropenia (12%). In arm B, main grade ≥3 toxicities were neutropenia (29%), fatigue (14%), peripheral neuropathy (7%). No toxic death were registered. Conclusions: Nab-FOLFIRI and Nab–FOLFOX demonstrated a similar activity to FOLFIRINOX, with better safety profile in terms of neutropenia, fatigue and neuropathy. These results could justify a future phase III evaluation. Clinical trial information: NCT02109341.

scholarly journals Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on an Ongoing Phase I/II Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3930-3930
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Ulrich Bitz ◽  
Christian Lerchenmueller ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Phase Iii ◽  
Mtor Inhibition ◽  
Grade 3 ◽  
Ongoing Phase

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. In relapsed MCL a phase III trial could prove superiority of Temsirolimus to standard options. Furthermore, in patients with follicular and diffuse large B-cell lymphoma, promising response rates could be observed (Smith et al, JCO 2010). Whereas combination to single agent Rituximab (R) improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information of the feasibility and efficacy in combination with chemotherapy. Bendamustine (B) has been shown to be effective in various lymphoma entities and has a beneficial side effect profile (Rummel et al, JCO, 2005). In the phase I of this trial, we have established that 50mg of Temsirolimus given 3 times weekly in a four week cycle could be safely added to BR (Hess, Leukemia, 2015). Here we report for the first time combined results of phase I and II of this trial. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven FL or MCL, 1-3 prior treatment lines, no curative option available, no refractoriness to Bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of Bendamustine 90mg/m² day 1-2, Rituximab 375mg/m² day 1 and Temsirolimus 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. Results: Overall 34 patients (pts) have been included until now (15 pts phase I, 19 pts phase II). Concerning clinical characteristics, median age was 71 years, with 25 MCL and 9FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 118 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (11 pts, 32%), neutropenia (8 pts, 24%), and thrombocytopenia (7 pts, 21%). Non-hematologic grade 3 / 4 observed in at least two patients were angioedema and decrease in blood potassium, infection, metabolic (4 events). AE's of special interest: pulmonary: rate of cough (4; 12%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (6; 18%), nausea (13, 38%); general: fatigue (16; 47%), mucositis (13, 38%); bleeding: epistaxis (4; 12%), which all were predominantly grade 1 or 2. Response: currently, best responses were 8 CR (31%), 16 PR (62%) and 2 SD (8%) in 26 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 94% in MCL (7 CR, 10 PR, 1 SD) and 88% in FL (1 CR, 6 PR, 1 SD). After a median follow up of 13 months (mean: 21 months) median PFS is 18.6 months for the entire cohort, with 22 months for MCL and not reached in FL. Summary: In this ongoing phase II trial 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab was well tolerated and feasible. A moderate dose of Temsirolimus to standard chemotherapy might be the optimal way to achieve the maximum efficacy with mTOR inhibitors; in fact excellent response rates suggest an additive effect of mTOR inhibition to BR. Even after the BTK inhibitor Ibrutinib has entered the clinical arena of MCL, this combined treatment represents a valuable additional option especially for patients with relapsed MCL Disclosures Hess: Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Witzens-Harig:Roche: Honoraria; Pfizer: Honoraria, Research Funding.

Natural history of diarrhea associated with the anti-CTLA4 monoclonal antibody CP-675,206

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3038-3038 ◽  
Author(s):  
S. Antonia ◽  
J. Sosman ◽  
J. M. Kirkwood ◽  
B. Redman ◽  
T. F. Gajewski ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Range ◽  
Objective Response ◽  
Stage Iv ◽  
Open Label ◽  
Similar Frequency ◽  
Severe Diarrhea ◽  
Grade 3 ◽  
Stage Iv Melanoma

3038 Background: Diarrhea resulting from immune activation has been associated with CTLA4 blockade. For example, in patients (pts) with stage IV melanoma receiving ipilimumab (MDX-010), a number of pts developed grade 3/4 autoimmune enterocolitis and severe diarrhea (Attia et al, 2005). In a single-dose phase I trial of CP-675,206 at doses up to 15 mg/kg in pts with solid tumors (n = 39), 9 instances of diarrhea were reported including 3 grade 3 events (Ribas et al, 2005). The incidence and severity of diarrhea was assessed in pts receiving CP- 675,206 in a large phase I/II study. Methods: An open-label phase I/II trial of CP-675,206 was conducted in pts with stage III (unresectable) or stage IV melanoma and an ECOG PS = 1. Diarrhea was assessed in pts treated at the phase II doses: 10 mg/kg monthly (Q1M) in phase I (n = 22), or 10 mg/kg Q1M (n = 44) or 15 mg/kg every 3 months (Q3M, n = 45) in phase II. Results: Medians of 3.5 doses (range, 1 to 18) at 10 mg/kg Q1M in phase I, 3 doses (range, 1 to 26) at 10 mg/kg Q1M in phase II, and 1 dose (range, 1 to 9) at 15 mg/kg Q3M were administered with 100% dose compliance. Treatment-related diarrhea was reported by 43 (39%) of 111 pts, and grade 3 diarrhea occurred in 14 (13%) pts. One patient had grade 4 colitis resulting in a colectomy. Diarrhea (all grades) occurred with similar frequency in each dose group; however, grade 3 treatment-related diarrhea occurred in 8% of pts treated with 15 mg/kg Q3M compared with 18% of pts treated with 10 mg/kg Q1M in phase I and 14% of pts treated with 10 mg/kg Q1M in phase II. Among 9 pts with an objective response, 8 experienced diarrhea (3 of which were grade 3). The majority of cases (65%) were mild to moderate in severity with a median time to onset of 51 days (range, 1 to 583 days) and resolution of 8 days (range, 1 to 182 days). More than half of pts who reported serious events of diarrhea were treated with steroids. Conclusions: Diarrhea associated with CP-675,206 was primarily mild to moderate in severity, transient, and manageable. In addition, 15 mg/kg Q3M may be better tolerated than 10 mg/kg Q1M. Ongoing clinical trials in pts with advanced melanoma will provide further information about the incidence, severity, and optimal management of diarrhea associated with CP-675,206. No significant financial relationships to disclose.

A phase I/II study of biweekly docetaxel (D) in combination with fixed-dose cisplatin plus fluorouracil (CF) in patients (pts) with advanced esophageal cancer (AEC) (JCOG0807).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15016-e15016
Author(s):  
Shuichi Hironaka ◽  
Yasuhiro Tsubosa ◽  
Junki Mizusawa ◽  
Takayuki Kii ◽  
Ken Kato ◽  
...  
Keyword(s):  
Phase I ◽  
Peer Review ◽  
Primary Endpoint ◽  
Performance Status ◽  
Treatment Compliance ◽  
Phase Iii ◽  
Fixed Dose ◽  
Open Label ◽  
Eligibility Criteria ◽  
Grade 3

e15016 Background: Thougha triplet chemotherapy with D plus CF (DCF) has shown promising activity, high incidence of adverse events (AEs) especially in febrile neutropenia (FN) was observed in previous studies for head and neck cancer (TAX323, 324) and gastric cancer (TAX325). To reduce its AEs with keeping activity, we conducted a multicenter open-label phase I/II study of biweekly D plus CF for AEC. Methods: Eligibility criteria included histologically proven AEC with measurable disease, age 20 to 75, non-resectable or recurrent disease, performance status (PS) 0 to 1. Pts received escalating doses of D (dose level (DL) 1: 30 mg/m2, DL 2: 40 mg/m2, on days 1, 15) in combination with fixed dose of CF (cisplatin 80 mg/m2 on day 1, fluorouracil 800 mg/m2on days 1-5) repeated every 4 weeks with 3+3 design in phase I part (P-I). The primary endpoint of P-I was dose limiting toxicity (DLT) and that of phase II part (P-II) was response rate (RR) defined by central peer review. Based on a SWOG two stage design (p0=35%, p1=50%; one-sided a=0.1, β =0.2) at least 22 responders among 50 eligible pts should be observed to satisfy the primary endpoint. Results: Between Feb 2009 and Mar 2010, 62 pts were enrolled for P-I and P-II. In P-I, 10 pts were enrolled with DLT of 0/3 in DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended dose for P-II was determined as DL1. Thus, 3 (P-I) and additional 52 pts (P-II) were analyzed: 53 for efficacy (excluded 2 ineligible pts) and 55 for safety. Pts characteristics were as follows: male/female 49/6, age median 61 (range 44 to 75), PS 0/1 39/16. The RR was 62% (95% confidence interval, 48-75%, p<0.0001) by central peer review. Median OS and PFS were 11.1 and 5.8 months. Grade 3/4 toxicity was observed in neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%) and nausea (11%). No grade 3/4 FN was observed. Treatment related death occurred in one patient due to pneumonitis. Conclusions: Biweekly D (30mg/m2) combined with CF showed promising activity and tolerability. A phase III study comparing CF with DCF is warranted. Clinical trial information: UMIN000001737.

scholarly journals Multicentre, Open Label, Randomized Phase III Study of Cpi-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 60 years) with Relapsed / Refractory Acute Myeloid Leukemia (AML) - Armada 2000 (AML003) Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2658-2658 ◽  
Author(s):  
Timothy S. Pardee ◽  
Sanjeev Luther ◽  
Marc E. Buyse ◽  
Bayard L Powell ◽  
Jorge E. Cortes
Keyword(s):  
Complete Remission ◽  
Phase I ◽  
Phase Ii ◽  
Older Patients ◽  
Research Funding ◽  
Phase Iii ◽  
High Dose ◽  
Open Label ◽  
High Dose Cytarabine ◽  
Refractory Aml

Background: Despite recent advances, outcome of patients with AML, particularly the older ones, remains poor. This is in part because of adverse features more frequently associated with AML in this patient population. Older patients with AML have high mortality (>90%). This is driven by the fact that over 50% of patients will experience a relapse, and most relapsed patients will die from AML within a year. There is no consensus standard treatment for relapsed or refractory disease, highlighting the high unmet need for these patients. Devimistat is a novel lipoic acid analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase. This inhibits mitochondrial respiration and cause hyper-phosphorylation of PDH and activation of adenosine monophosphate activated kinase (AMPK) in AML cells. The ARMADA 2000 trial seeks to leverage the unique mechanism of action of this agent to improve the outcomes for older patients suffering from relapsed or refractory AML. To date devimistat has been given to more than 108 relapsed or refractory AML patients in multiple clinical trials (phase I and phase II). These studies suggest that devimistat can be safely combined with high dose cytarabine and mitoxantrone in relapsed or refractory AML patients. The possible beneficial effect in older patients was demonstrated by the dose response relationship seen in older but not younger patients. The combined efficacy result from 23 treated patients (≥ 60 years) on either of phase I or phase II studies of devimistat and high dose cytarabine and mitoxantrone (CHAM) showed complete remission (CR) rate of 48%, CR + CRi of 52% and median overall survival (OS) of 12.4 months [interim result of this study was presented at EHA Annual Meeting 2018, for further details please refer: Analysis of phase I and pilot phase II data reveal 2,000 mg/m2 as the optimal dose of CPI-613 in combination with cytarabine and mitoxantrone for elderly patients with relapsed or refractory AML]. Given the favorable safety profile of CHAM with the promising response results achieved in these trials, further evaluation of devimistat in AML is warranted. The current study evaluates devimistat in combination with high dose cytarabine and mitoxantrone (CHAM) in older patients with relapsed or refractory AML. Method: This is a multicentre, open label, randomized phase III study of devimistat in combination with high dose cytarabine and mitoxantrone (CHAM) compared to high dose cytarabine and mitoxantrone (HAM) in older patients with relapsed/refractory AML. Eligible patients are male and female individuals who are 60 years and older with histologically documented AML that is relapsed from, or refractory to, prior standard therapies that include standard dose cytarabine or high dose cytarabine based induction cycle or no response after at least 3 cycles of a hypomethylating agent with or without venetoclax. Other key inclusion criteria include ECOG performance status 0-2 and expected survival >3 months. A total of 500 patients will be randomized in a 1:1 fashion between arms. Following completion of all planned induction and/ or consolidation therapy cycles, patients in remission on the CHAM arm will continue to receive devimistat during maintenance cycle(s) until disease recurrence, availability of stem cell transplant, the advent of intolerable side effects, or patient withdrawal of consent. Primary endpoint of the study is complete remission (CR) of CHAM compared to HAM. Secondary endpoints include overall survival (OS), complete remission with partial hematologic recovery (CRh) and safety. Exploratory analysis will examine the expression of a gene signature from baseline marrow samples found to be predictive of response in the phase I study. Additional analysis will correlate the expression of several key proteins including PDH, KGDH, PDK1-4, SOD2 and CD79a in baseline marrow samples with response. Statistical analysis plan for this trial is summarized in Table 1 and Table 2. This study was initiated in November 2018 and planned at approximately 87 sites in more than 13 countries, recruiting 500 patients. The interim analysis of the study is expected to be completed as early as Q3 2020. Clinical trial information: NCT03504410 Disclosures Pardee: Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Spherix Intellectual Property: Research Funding. Luther:Rafael Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Buyse:Rafael Pharmaceuticals: Consultancy. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Devimistat is not approved by the FDA for any indication and the clinical trial describes its use in AML.

Survival of patients (pts) with metastatic melanoma treated with the anti-CTLA4 monoclonal antibody (mAb) CP-675,206 in a phase I/II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8524-8524 ◽  
Author(s):  
J. Gomez-Navarro ◽  
S. Antonia ◽  
J. Sosman ◽  
J. M. Kirkwood ◽  
B. Redman ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Median Survival ◽  
Phase Ii ◽  
Survival Data ◽  
Phase I Study ◽  
Objective Response ◽  
Phase Iii ◽  
Open Label ◽  
Expansion Cohort

8524 Background: The fully human anti-CTLA4 mAb CP-675,206 has demonstrated clinical activity in pts with metastatic melanoma. Prolonged survival was observed in a prior single-dose phase I study, even in pts who did not achieve objective tumor responses. Methods: A multidose phase I/II trial was conducted in pts (N = 119) with histologically confirmed stage IIIc (unresectable) or stage IV recurrent metastatic melanoma and ECOG PS = 1. The study consisted of a phase I, open-label, multidose study (3, 6, and 10 mg/kg) and a phase I expansion cohort for HLA-A2.1+ pts (10 mg/kg monthly [Q1M]), followed by a phase II open-label study of 2 dosing regimens: 10 mg/kg Q1M and 15 mg/kg every 3 months (Q3M). The primary endpoint was safety in phase I, immune monitoring in the expansion cohort, and response in phase II. Survival was analyzed as a secondary endpoint. Results: In the phase I study, Kaplan-Meier estimates of median overall survival were 17.6 months for all dose groups combined (n = 28). In the phase II study, median survival was 10.3 months in the 10 mg/kg arm and 11.0 months in the 15 mg/kg arm. Survival outcomes were favorable, compared with historical median survival of 7 months, independent of whether pts achieved an objective response. Updated survival data will be presented. Conclusions: Patients participating in a multiple dose study of CP-675,206 showed a survival time that was greater than expected on historic controls. These observations support the endpoints of an ongoing randomized phase III study in melanoma to further evaluate survival in the frontline setting. [Table: see text] [Table: see text]

A phase I/II study (TaxXel) on the treatment with docetaxel in combination with capecitabin in patients with metastatic esophageal cancer or cancer in the cardia region.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14531-e14531
Author(s):  
Signe Friesland ◽  
Gun Wickart-Johansson ◽  
Lianna Kadar ◽  
Charlotte Bratthall ◽  
Henry Letocha ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Response Rate ◽  
Tumour Progression ◽  
Primary Objective ◽  
Open Label ◽  
Multicenter Phase ◽  
Grade 3 ◽  
Rapid Tumour

e14531 Background: This is an open label, non-randomized, multicenter phase I-II study with Docetaxel (Doc) given in combination with capecitabine (Cap) in patients (pts) with metastatic oesophageal cancer (mEC) or cancer in the cardia region (mCCR). Methods: In phase I, pts were treated with Cap day 1-14, 22-36 and Doc day 1, 8, 15, 22, 29. Cap was dose escalated from 1300 mg up to 1650mg/m2 per day according to modified Fibonacci design. The dose of Doc was fixed to 30mg/m2 in both Phase I-II. In Phase II 1650mg/m2 Cap was given. The primary objective in phase I was to define a dose of Cap recommended for the Phase II and to determine the feasibility and safety of this treatment. The primary objective in the phase II was to determine the response rate (RR), safety profile, quality of life and survival.The median age was 64.8 years, PS was 0 in 23 pts, I in 57 and II in 13 pts. The histology was as follows: 58 adenoca, 33 squamous cell ca and 2 poorly diff ca. Forty-three pts had previously been treated with chemotherapy, 41 with radiotherapy, 50 were chemotherapy-naive and 31 had underwent surgery. Results: From March 2006 to Oct 2010, 93 eligible pts with measurable disease were enrolled in the study. Fourteen were treated in phase I and 79 in phase II. Four pts (1 in ph I and 3 in ph II) did not receive any study treatment. Twenty-seven pts of 93 (29%) were not evaluable according to study protocol which included CT after 6 w of treatment due to rapid tumour progression and deterioration of general condition. RR was 29%, 2 CR and 25 PR, 15 pts (16%) had SD and 24 pts (26%) had PD. Median OS was 7.3 months (5.76-8.9) and median PFS was 4.2 months (2.3-4.7 months).Treatment related grad 3 or 4 toxicity was as follows: 60% of pts experienced any grade 3 or 4 toxicity, 30% related to infections, 24% had nausea, diarrhea, vomiting, mucositis, <10% had cardiac related symptoms, <1% had an allergic reaction to Doc. Conclusions: Cap together with Doc appears tolerable and has a RR of 29% in selected group of patients with mET and mCCR. Majority of treatment courses were given on out-patient bases. However, there is un urgent need to define an optimal therapy regime and further studies are warranted.

Phase II study of gemcitabine, cisplatin, and sunitinib (S) in patients with advanced urothelial carcinoma (UC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 282-282 ◽  
Author(s):  
Matt D. Galsky ◽  
Beth A. Hellerstedt ◽  
Mark Allen O'Rourke ◽  
Nicholas J. Vogelzang ◽  
Darren M. Kocs ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Urothelial Carcinoma ◽  
Phase Ii ◽  
Single Agent ◽  
Dosing Regimen ◽  
Serious Adverse Events ◽  
G 12 ◽  
Advanced Urothelial Carcinoma ◽  
Grade 3 ◽  
Dose Reductions

282 Background: Sunitinib (S) has single-agent activity in patients with advanced urothelial carcinoma (UC). Preclinical studies in UC demonstrate at least additive antitumor activity combining S with gemcitabine (G) or cisplatin (C). Methods: Patients with chemonaïve metastatic UC were enrolled in a multicenter phase II trial with overall response rate (ORR) as the primary endpoint. The initial dosing regimen, based on a phase I trial (Reck, 2010), was G 1000 mg/m2 IV (Days 1 & 8), C 70 mg/m2 IV (Day 1), and S 37.5 mg PO daily (Days 1-14)/each 21-day cycle (up to 6 cycles), followed by S 37.5 mg daily until progression. Results: From December 2008 to August 2009, 15 eligible patients enrolled. Seven of 15 patients discontinued treatment early (median: 3 cycles) due to toxicity, most often due to recurrent neutropenia and thrombocytopenia. Intrapatient dose reductions were required for G (12/15), C (8/15), and S (10/15). Eight of 15 patients experienced serious adverse events. Based on the toxicity profile, enrollment was held and the dosing regimen was revised to G 800 mg/m2 IV (Days 1 and 8), C 60 mg/m2 IV (Day 1), S 37.5 mg PO daily (Days 1-14). From December 2009 to April 2011, 18 additional patients were enrolled. Despite the reduced starting doses, intrapatient dose reductions were required for G (13/18), C (9/18), and S (15/18). The most frequent Grade 3-4 toxicities for both groups were neutropenia (70%), thrombocytopenia (58%), and anemia (30%). Antitumor activity is shown in the Table. Median PFS was 7.9 and median OS was 13.8 months. Conclusions: Combination G+C+S is poorly tolerated and results in activity comparable to historical results with G+C alone. Supported in part by a grant from Pfizer Inc. [Table: see text]

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