scholarly journals Combination immunotherapy with nivolumab and ipilimumab in patients with rare gynecological malignancies: results of the CA209-538 clinical trial

2021 ◽  
Vol 9 (11) ◽  
pp. e003156
Author(s):  
Oliver Klein ◽  
Damien Kee ◽  
Bo Gao ◽  
Ben Markman ◽  
Jessica da Gama Duarte ◽  
...  
Keyword(s):  
Disease Control ◽  
Response Rate ◽  
Cytotoxic T Lymphocyte ◽  
Treatment Options ◽  
Objective Response ◽  
Induction Treatment ◽  
Clinical Activity ◽  
Combination Immunotherapy ◽  
Gynecological Cancers ◽  
Gynecological Malignancies

BackgroundPatients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers.MethodsThis multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB).ResultsThe objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB.ConclusionsIpilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.

scholarly journals PD-1 Blockade in Advanced Adrenocortical Carcinoma

2020 ◽  
Vol 38 (1) ◽  
pp. 71-80 ◽  
Author(s):  
Nitya Raj ◽  
Youyun Zheng ◽  
Virginia Kelly ◽  
Seth S. Katz ◽  
Joanne Chou ◽  
...  
Keyword(s):  
Objective Response Rate ◽  
Response Rate ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Programmed Death Ligand 1 ◽  
Prior Therapy ◽  
Programmed Death ◽  
Adrenocortical Carcinomas

PURPOSE Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC. PATIENTS AND METHODS Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates. RESULTS We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response. CONCLUSION MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.

Combination immunotherapy with ipilimumab and nivolumab in patients with advanced biliary tract cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4588-4588
Author(s):  
Oliver Klein ◽  
Damien Kee ◽  
Adnan Nagrial ◽  
Ben Markman ◽  
Craig Underhill ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Biliary Tract ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Clinical Activity ◽  
Combination Immunotherapy ◽  
Biliary Tract Cancers ◽  
Mutation Burden ◽  
Duration Of Response

4588 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with first and second line chemotherapy resulting in modest survival benefits. Immunotherapy using single agent anti-PD-1 therapy has also shown low activity with an objective response rate (ORR) of less than 10%. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell carcinoma. To date, no trials in BTC pts with ipi/nivo therapy have been reported. Methods: 39 pts with metastatic BTCs were enrolled into the CA 209-538 clinical trial for rare cancers. Patients received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for 4 doses, followed by nivo 3mg/kg q 2 weekly. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers including PD-L1 expression and tumour mutation burden. Results: 39 pts with BTC were enrolled and 33 pts (85%) had received at least one prior line of systemic treatment (0-2 lines). The ORR was 24% and the CBR 45% with the median duration of response not been reached (range 2-26+months). Responses were observed in 3/14 intrahepatic, 1/10 extrahepatic, 0/2 unspecified cholangiocarcinoma and 5/13 gallbladder ca pts. None of the responding pts had a microsatellite instable tumour. 2 pts with durable partial responses were subsequently rendered surgically free of disease. Median OS and PFS were 6.1 and 3.1 months respectively. 22 (56%) pts experienced an immune –related adverse event (irAE) with grade3/4 irAEs being observed in 8 (20%) pts. Conclusions: Combination immunotherapy with ipi/nivo demonstrates significant clinical activity in a subset of patients with advanced microsatellite stable BTC. The response rate compares favourably to clinical trials investigating single agent anti-PD-1 therapy. Clinical trial information: NCT02923934 .

scholarly journals Effect and Safety of Anti-PD-1/PD-L1 Monotherapy for Metastatic Breast Cancer: A meta-analysis

2019 ◽  
Author(s):  
Yihang Qi ◽  
Xiangyi Kong ◽  
Xiangyu Wang ◽  
Jie Zhai ◽  
Yi Fang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Survival Rate ◽  
Response Rate ◽  
Meta Analysis ◽  
Treatment Options ◽  
Metastatic Breast ◽  
Clinical Activity ◽  
Breast Cancer Patients ◽  
Severe Grade

Abstract Background. Given that no approved targeted agents for metastatic triple-negative breast cancer (mTNBC) and no opportunity of surgery for metastatic breast cancer (MBC), new treatment options are urgently to be discovered. The anti-PD-1/PD-L1 immunotherapy may be effective, and what we should be aware of is the response rate and adverse events. Methods. The PUBMED, EMBASE, Cochrane and www.clinicaltrials.gov databases were searched to find potential studies using the following strategies: anti-PD-1/PD-L1; metastatic; breast cancer. R© package Meta was used to pool incidence. Results. Six studies including 586 advanced breast cancer patients treated with anti-PD-1/PD-L1 agents were included in this meta-analysis. The anti-PD-1/PD-L1 agents include pembrolizumab, atezolizumab and avelumab. Among these patients, CR was 1.26%, PR was 7.65%, ORR was 9.85% and DCR was 18.33%. We also found that the response rate was closely associated with the expression of PD-L1 biomarker (PD-L1+ vs PD-L1-): the CR was 2.71% vs 0.00%; the PR was 9.93% vs 2.69%; the ORR was 10.62% vs 3.07%; the DCR was 17.95% vs 4.71%. 1-year overall survival rate and 6-months progression-free survival rate were 43.34% and 17.24%. Respectively, the overall incidence of AEs was 64.18% in any grade and 12.94% in severe grade. The incidence of irAEs was 14.75%. Besides, the incidence of discontinue and death due to treatment-related AEs was about 3.06% and 0.31% respectively. When the detailed AEs were analyzed, most treatment-related AEs of any grade were arthraigia, asthenia, decreased appetite; most common treatment-related AEs of severe grade were anemia, autoimmune hepatitis, diarrhea; the most common irAEs were hypothyroidism , followed by hyperthyroidism, pneumonitis and infusion-related reaction. Conclusions. Anti-PD-1/PD-L1 monotherapy showed a manageable safety profile and had a durable anti-tumor clinical activity in a subset of patients with mTNBC or MBC. PD-L1 expression may be correlated to a higher probability of clinical response.

Efficacy of targeted therapy in alveolar soft part sarcoma: A systematic review and meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e23543-e23543
Author(s):  
Na Hyun Kim ◽  
Chenyu Sun ◽  
Apurwa Prasad ◽  
Humaed Mohammed Abdul ◽  
Saba Batool ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Disease Control ◽  
Randomized Clinical Trials ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Soft Part ◽  
Objective Response ◽  
Chromosome 17 ◽  
Alveolar Soft Part Sarcoma

e23543 Background: Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma, characterized by a specific unbalanced translocation leading to the fusion of the TFE3 gene on chromosome-X to the ASPSCR1 gene on chromosome-17. Despite its indolent course, ASPS presents a challenge in treatment due to its resistance to conventional anthracycline-based chemotherapy and lack of large scale trial data for this rare sarcoma. This review aimed to assess the efficacy of tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) in metastatic alveolar soft part sarcoma. Methods: A systematic search was performed on Embase and Medline databases for studies that assessed best response of patients with unresectable or metastatic ASPS to TKI and ICI therapy, according to the Response Evaluation Criteria in Solid Tumors (RECIST) edition 1.0 or 1.1. This study followed the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol. Four independent reviewers screened abstracts and extracted the data; any discrepancy was resolved by discussion among reviewers. Pooled objective response rate (ORR) and disease control rate (DCR) were obtained using the Freeman-Tukey double-arcsine transformation using random effects model on STATA software (version. 16.1, StataCorp). Results: 27 articles and abstracts published between 2011 and 2020 were included in the review, resulting in 2 randomized clinical trials (104 participants), 14 single arm prospective trials (214 participants), and 11 retrospective studies (120 patients). Among clinical trials, the pooled ORR and DCR were 18% (95% confidence interval [CI] 8 - 30%; I2 = 72.25%; p < 0.01) and 87% (95% CI 97 - 93%; I2 = 43.2%; p = 0.03) respectively. Conclusions: The response rate to targeted therapy in metastatic ASPS is not only clinically meaningful, but also comparable to that of first-line chemotherapy. The majority of patients receiving targeted therapy achieved disease control. Patients who had refractory or progressive disease to one targeted agent demonstrated response to other agents. More randomized trials are warranted to expand treatment options and compare to standard of care regimens.

scholarly journals Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma: Preliminary Toxicity and Activity Data in Dogs

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1272 ◽  
Author(s):  
Laura Marconato ◽  
Silvia Sabattini ◽  
Giorgia Marisi ◽  
Federica Rossi ◽  
Vito Ferdinando Leone ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Safety Profile ◽  
Median Overall Survival ◽  
Response Rate ◽  
Treatment Options ◽  
Objective Response ◽  
Metronomic Chemotherapy ◽  
Time To Progression ◽  
Activity Data

Unresectable nodular and diffuse hepatocellular carcinoma (HCC) have a poor prognosis with limited treatment options. Systemic traditional chemotherapy has been only rarely reported, with unsatisfactory results. The aim of this prospective, non-randomized, non-blinded, single center clinical trial was to investigate safety profile, objective response rate, time to progression and overall survival of sorafenib in comparison with metronomic chemotherapy (MC) consisting of thalidomide, piroxicam and cyclophosphamide in dogs with advanced, unresectable HCC. Between December 2011 and June 2017, 13 dogs were enrolled: seven received sorafenib, and six were treated with MC. Median time to progression was 363 days (95% CI, 191–535) in dogs treated with sorafenib versus 27 days (95% CI, 0–68) in dogs treated with MC (p = 0.044). Median overall survival was 361 days (95% CI, 0–909) in dogs receiving sorafenib, while 32 days (95% CI, 0–235) in those receiving MC (p = 0.079). Sorafenib seems to be a good candidate for the treatment of dogs with advanced HCC, due to a benefit in disease control and an acceptable safety profile, offering a good basis on which new randomized prospective clinical trials should be undertaken to compare the efficacy and drawback of sorafenib versus MC or traditional chemotherapy.

Phase II study of irinotecan and paclitaxel for patients with recurrent small cell lung cancer (SCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18011-18011
Author(s):  
T. K. Owonikoko ◽  
S. Ramalingam ◽  
J. Forster ◽  
Y. Shuai ◽  
T. Evans ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Treatment Options ◽  
Objective Response ◽  
Ecog Performance Status ◽  
Stage Design ◽  
Prior Chemotherapy Regimen ◽  
Version 2.0

18011 Background: Recurrent SCLC has a poor prognosis and is devoid of treatment options that improve overall survival. Irinotecan and paclitaxel are both active agents against SCLC, and have synergistic preclinical interactions. We conducted a phase II study to evaluate the efficacy and safety of the combination of irinotecan and paclitaxel for patients with recurrent SCLC. Methods: Patients with SCLC who relapsed following one prior chemotherapy regimen were eligible. Other pertinent inclusion criteria were: ECOG performance status 0–2, adequate bone marrow, hepatic and renal function and willingness to provide informed consent. Patients with untreated brain metastasis were excluded. Paclitaxel (75 mg/m2) and irinotecan (50 mg/m2) were administered on days 1 & 8 of every 3-week cycle. Treatment was continued until progression up to a maximum of 6 cycles or unacceptable toxicity. The primary endpoint was response rate. Toxicity was graded by CTC version 2.0. The simon two-stage design was utilized and the estimated sample size was 55 patients (stage I - 23 patients; stage 2 - 32 patients). The study has a 90% power to detect a response rate of 30%, with an alpha error rate of 10%. Results: 55 patients have been enrolled and complete data are available for 32 patients at the time of this report. Patient baseline characteristics are: male 53%, PS 0–44%; PS 1–47% and PS 2–6%. The median age is 61 years. Fifteen patients received ≥ 4 cycles. Salient grades 3–5 toxicities seen: neutropenia (13%), fatigue (13%); diarrhea (3%), hypersensitivity (3%) and hyponatremia (3%).The objective response rate is 37% (95% CI 19%-55%) with 9 PRs and 1 CR. Additional 8 patients (24%) had stable disease. The median survival is 19.6 weeks (95% CI 15.1–29.4) and the 1-year survival rate is 15%. Conclusions: The combination of irinotecan and paclitaxel is well tolerated and has promising anti-cancer activity in recurrent SCLC. Updated data on all 55 patients will be available at the time of the presentation. No significant financial relationships to disclose.

Effect of ipilimumab at 10 mg/kg on disease control in patients (pts) with M1c-stage melanoma in relation to baseline lactate dehydrogenase (LDH) levels

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9041-9041
Author(s):  
M. Smylie ◽  
S. Francis ◽  
B. Neyns ◽  
M. Maio ◽  
D. Minor ◽  
...  
Keyword(s):  
Disease Control ◽  
Phase Ii ◽  
Cytotoxic T Lymphocyte ◽  
Stage Iv ◽  
Tumor Burden ◽  
Clinical Activity ◽  
Melanoma Metastasis ◽  
Phase Ii Studies ◽  
Similar Disease ◽  
To Receive

9041 Background: Ipilimumab, a fully human, anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody, enhances antitumor immunity. Ipilimumab is clinically active in advanced melanoma, with a 1-year survival rate of ∼50% in Phase II studies (Wolchok et al. CRI-CVC annual meeting 2008. Oral presentation). Serum LDH level is an independent prognostic factor for malignant melanoma, and is strongly predictive of reduced survival in stage IV disease (Bedikian et al. J Clin Oncol. 2006;24:4738–4745.). This analysis evaluated the association between baseline LDH levels and disease control (stable or reduced measurable tumor burden) in previously treated pts with M1c-stage melanoma (metastasis to vital organs other than the lungs) who received ipilimumab in 2 recently completed Phase II studies (CA184008 and 022). Methods: Ipilimumab at 10 mg/kg was given every 3 weeks (Q3W) × 4; eligible pts could continue to receive ipilimumab Q12W beginning at Week 24. In study 022, pts were randomized to receive ipilimumab induction dosing at 0.3, 3.0, or 10 mg/kg Q3W × 4; study 008 was a single- arm trial of ipilimumab at 10 mg/kg. Disease control data were pooled from the 2 Phase II studies for pts treated with ipilimumab at 10 mg/kg and stratified by normal and elevated (>1× upper normal limit [UNL]) LDH levels. Elevated LDH was not capped. Results: For 227 pts treated at 10 mg/kg, 123 had M1c-stage disease: 42 had normal LDH and 81 had LDH >1 × UNL (of which 32 had LDH 2 × UNL). Among these 123 pts, 17/81 (21.0%) [95% CI 12.7–31.5] with elevated LDH levels experienced disease control, whereas 12/42 (28.6%) [95% CI 15.7–44.6] with LDH levels at or below the UNL experienced disease control. Conclusions: Our data show that ipilimumab exerts similar disease control in pts with normal and elevated LDH levels. Ipilimumab therefore appears to have clinical activity in the form of disease control in pts with a very poor prognosis, i.e., M1c-stage melanoma and elevated LDH levels. [Table: see text]

A phase II trial of salvage treatment with gemcitabine and S-1 combination in heavily pretreated patients with metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3595-3595
Author(s):  
Sun Jin Sym ◽  
Junshik Hong ◽  
Hee Kyung Ahn ◽  
Jinny Park ◽  
Eun Kyung Cho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Heavily Pretreated

3595 Background: We conducted a phase II trial of gemcitabine with S-1 to evaluate the activity and toxicity of such a combination in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after treatment with fluoropyrimidines-, oxaliplatin- and irinotecan-containing regimens. Methods: 36 pts were enrolled, with the following characteristics: 19 females (53%), median age 57 (28-72), 30 EOGO PS 0-1 (83%). S-1 was given orally (30 mg/m2) b.i.d for 14 consecutive days and gemcitabine (1000 mg/m2) was given on days 1 and 8, every 21 days, until disease progression and for a maximum of 9 cycles. The primary endpoint was objective response rate (ORR). Results: The median number of cycles was 5 (range 1-9), ORR was 16.7% (95% confidence interval [CI] 4.5-28.9%) and disease control rate was 61.1% (95% CI 45.2-77.0%) with 6 partial responses and 16 stable diseases. Median duration of disease control was 5.8 months (95% CI 4.1-7.5 months). Median progression-free survival was 3.7 months (95% CI 2.2-5.2 months) and median overall survival was 10.0 months (95% CI 7.4-12.7 months). Grade 3-4 toxicities were rare (neutropenia 12%, anemia 11%, leucopenia 6%, thrombocytopenia 3% and diarrhea 3%). Conclusions: Combination chemotherapy with gemcitabine and S-1 was a convenient, well tolerated and efficacious for heavily pre-treated pts with mCRC. This regimen warrants further evaluation in pts with good PS but no further treatment options.

A phase II trial of salvage treatment with gemcitabine and S-1 combination in heavily pretreated patients with metastatic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 488-488 ◽  
Author(s):  
Sun Jin Sym ◽  
Junshik Hong ◽  
Hee Kyung Ahn ◽  
Jinny Park ◽  
Eun Kyung Cho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Ecog Ps

488 Background: We conducted a phase II trial of gemcitabine with S-1 to evaluate the activity and toxicity of such a combination in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after treatment with 5-fluorouracil (5-FU), oxaliplatin and irinotecan. Methods: 34 pts were enrolled, with the following characteristics: 17 (50%) females, median age 57 years (28-72), 28 (82%) ECOG PS 0-1. S-1 was given orally (30 mg/m2) b.i.d for 14 consecutive days and gemcitabine (1000 mg/m2) was given on days 1 and 8, every 21 days, until disease progression and for a maximum of 9 cycles. The primary endpoint was objective response rate (ORR). Results: The median number of cycles was four (range 1-9). ORR was 14.7% (95% confidence interval [CI] 2.8-26.6) and disease control rate was 58.8% (95% CI 42.2-75.3) with five partial responses and fifteen stable diseases. Median duration of disease control was 5.1 months (95% CI 3.3-7.0). Median progression-free survival was 3.2 months (95% CI 2.3-4.1) and median overall survival was 11.8 months (95% CI 7.0-16.5). Grade 3-4 toxicities were neutropenia (12%), anemia (12%), thrombocytopenia (3%) and diarrhea (3%). Conclusions: Combination chemotherapy with gemcitabine and S-1 was well tolerated and efficacious for heavily pre-treated mCRC pts, and could be an alternative for pts with good PS but no further treatment options.

The mitochondrial metabolism inhibitor CPI-613 in combination with mFOLFIRINOX for pancreatic adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 264-264
Author(s):  
Angela Tatiana Alistar ◽  
Rodwige Desnoyer ◽  
Ralph D'Agostino
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Phase I ◽  
Response Rate ◽  
Treatment Options ◽  
Objective Response ◽  
Stage Iv ◽  
Phase I Clinical Trial ◽  
Glutamine Metabolism ◽  
Metastatic Pancreatic Cancer

264 Background: Stage IV pancreatic cancer is a lethal disease with limited treatment options. Current standard practice is combination chemotherapy with FOLFIRINOX or Gemcitabine + Abraxane. Despite these two new treatment options, the response rate and survival are limited in stage IV pancreatic cancer. The glycolic and mitochondrial metabolisms are aberrant in pancreatic cancer and translate into chemo-resistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as chemotherapy. CPI -613 is a novel anti-mitochondrial developed by Cornerstone Pharmaceuticals. Methods: A phase I clinical trial with mFOLFIRINOX+ CPI-613 in never treated for stage IV pancreatic cancer patients was initiated. The goals of this phase 1trial are: (1) To determine the Maximum Tolerated Dose (MTD) of CPI-613, when used in combination with mFOLFIRINOX, in patients with metastatic pancreatic cancer, (2) To assess the safety of CPI-613/ mFOLFIRINOX combination in patients with metastatic pancreatic cancer, and (3) To obtain preliminary data on efficacy of treatment with CPI-613/ mFOLFIRINOX Results: The MTD for CPI 613 was identified at 500mg/m2. The treatment combination is feasible and well-tolerated. The combination treatment was not found to have higher toxicity than FOLFIRINOX alone. The objective response rate was 53.9 % which is higher than FOLFIRINOX alone (reported as 31.6%). One patient has a complete radiologic and clinical response and two other patients have near complete responses. Conclusions: The preliminary efficacy data of this phase I clinical trial will inform a multi-institutional randomized phase II study of FOLFIRINOX vs. m FOLFIRINOX+ CPI613 in the near future. Clinical trial information: NCT01835041.

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