Study of CBP501/Cisplatin/Nivolumab Combinations in Advanced Pancreatic Cancer

Multicenter, Randomized, Parallel Group, Phase 2 to Establish the Efficacy and Safety of Combinations of CBP501, Cisplatin, and Nivolumab for ≥3rd Line Treatment of Patients With Exocrine Pancreatic Cancer and WBC <10,000/mm3 at Screening

Multicenter, randomized, open-label, parallel group phase 2 study to assess the efficacy and tolerance of four combinations of CBP501, cisplatin, and nivolumab administered once every 21 days to patients with stage IV exocrine pancreatic cancer and WBC < 10,000/mm3 at screening.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer Stage IV
• Intervention / Treatment: Drug: Nivolumab; Drug: CBP501 (25); Drug: Cisplatin; Drug: CBP501 (16)

Detailed Description

Multicenter, randomized, open-label, parallel group phase 2 study to assess the efficacy and tolerance of four combinations of CBP501, cisplatin, and nivolumab administered once every 21 days to patients with stage IV exocrine pancreatic cancer and WBC < 10,000/mm3 at screening. Patients will be randomized 1:1:1:1 to the following four treatment groups, with randomization stratified by ECOG PS (0 vs 1) and liver metastasis (present vs absent):

1. CBP501 25 mg/m2 + cisplatin 60 mg/m2 + nivolumab 240 mg
2. CBP501 16 mg/m2 + cisplatin 60 mg/m2 + nivolumab 240 mg
3. CBP501 25 mg/m2 + cisplatin 60 mg/m2
4. Cisplatin 60 mg/m2 + nivolumab 240 mg No more than 4 cycles of combination therapy may be administered but patients who remain progression-free after 4 cycles may receive up to 6 additional cycle of single-agent nivolumab.

A Fleming two-stage design will be used. For each study arm, the null hypothesis that the true percentage of patients progression-free at 3 months is 10% will be tested against a one-sided alternative. In the first stage, 9 patients will be accrued to each study arm. In the first stage, if there are 1 or fewer patient progression-free at 3 months the study will be stopped for futility and if there are 4 or more patients progression-free at 3 months the study will stopped and the null hypothesis rejected. Otherwise, 14 additional patients will be accrued to the study arm for a total of 23. The null hypothesis will be rejected if 6 or more of 23 patients are progression-free at 3 months. This design yields a type I error rate of 2.5% and power of 80% when the true percentage of patients progression-free at 3 months is 35%.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Arizona Oncology Associates, PC-Hope
  • California
    • Los Angeles, California, United States, 70121
      • Ochsner Clinic Foundation
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
  • Delaware
    • Newark, Delaware, United States, 19713
      • Medical Oncology Hematology Consultants, PA
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Illinois Cancer Specialists
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Minnesota Oncology Hematology, P.A.
  • Nevada
    • Henderson, Nevada, United States, 89052
      • James D Sanchez
  • Ohio
    • Cincinnati, Ohio, United States, 45245
      • Oncology Hematology Care, Inc.
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology-Austin Midtown
    • Dallas, Texas, United States, 75246
      • Texas Oncology-Baylor Charles A. Sammons Cancer Center
    • Dallas, Texas, United States, 75230
      • Mary Crowley Medical Research Center
    • McAllen, Texas, United States, 78503
      • Texas Oncology-McAllen South Second Street
    • McKinney, Texas, United States, 75071
      • Texas Oncology- Mckinney
    • San Antonio, Texas, United States, 78217
      • Texas Oncology-San Antonio Northeast
    • Temple, Texas, United States, 76508
      • Baylor Scott & White Medical Center
    • Tyler, Texas, United States, 75702
      • Texas Oncology-Northeast Texas
  • Virginia
    • Arrington, Virginia, United States, 22205
      • Virginia Cancer Specialists, PC
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists, P.C.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent obtained prior to initiation of any study-specific procedures and treatment;

2. Patients with pathologically confirmed stage IV exocrine pancreatic cancer who have received at least two lines of systemic therapy for metastatic disease. Up to 10 of prior lines of systemic therapy (including prior cisplatin), chemoradiotherapy, radiotherapy or investigational agents the patient has received are allowed in order to be eligible, as long as all eligibility criteria are met, with the exception that a patient must not have received more than two prior lines incorporating anti-PD-1, anti-PD-L1, or anti-CTLA-4 immune checkpoint blockade.

   Patients who have received prior anti-PD-1, anti-PD-L1, or anti-CTLA-4 immune checkpoint blockade therapy must have tolerated therapy with no evidence of grade 4 toxicity or an immune-related event (any grade) that required treatment discontinuation. Patients who experienced an endocrine related dysfunction are eligible, provided they are on stable hormone replacement therapy;

3. Male or female patients aged ≥ 18 years at time of informed consent;
4. ECOG Performance Status (PS) 0-1;
5. Life expectancy > 3 months;
6. Previous anticancer treatment must be discontinued at least 3 weeks prior to the initiation of study treatment (with the exception of 6 weeks for mitomycin C; 6 weeks for anti-androgen therapy if discontinued prior to treatment initiation, and 8 weeks for bicalutamide);

7. Adequate bone marrow reserve, cardiac, liver, renal and metabolic function:

   • white blood cell count (WBC) <10,000/mm3;
   • absolute neutrophil count (ANC) ≥ 1,500/mm3;
   • platelet count ≥ 100,000/mm3;
   • hemoglobin ≥ 9 g/dL;
   • creatinine phosphokinase isozymes CPK-MB and CPK-MM ≤ upper limit of normal (ULN);
   • serum troponin T levels within normal limits;
   • bilirubin ≤ 1.5 x ULN;
   • alanine aminotransferase (ALT, SGPT) and aspartate aminotransferase (AST, SGOT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present);
   • INR ≤ 1.5 x ULN;
   • serum creatinine ≤ ULN or creatinine clearance ≥ 60 mL/min (by Cockcroft & Gault formula or alternate calculation by 24hr urine collection). Patients with serum creatinine ≤ ULN and clearance between 45 to 59 mL/min should reduce cisplatin dose by 50%;
   • serum potassium ≥ 3.0 and ≤ 5.5 mmol/L;
   • serum calcium ≥ 8.0 and ≤ 11.5 mg/dL (≥ 2.0 and ≤ 2.9 mmol/L);
   • serum magnesium ≥ 1.2 and ≤ 3.0 mg/dL (≥ 0.5 and ≤ 1.23 mmol/L);
8. Female patients of child-bearing potential must have a negative serum pregnancy test and use at least one form of contraception as approved by the investigator for 4 weeks prior to initiating study treatment and for 14 months after the last dose of study drug . For the purposes of this study, child-bearing potential is defined as "all female patients unless they are post-menopausal for at least 3 years or surgically sterile;
9. Male patients must use a form of barrier contraception approved by the investigator during the study and for 14 months after the last dose of study drug.
10. Ability to cooperate with study treatment and follow-up.

Exclusion Criteria:

1. Radiation therapy to >30% of bone marrow prior to study entry;
2. Prior chemotherapy with nitrosoureas, prior mitomycin C cumulative dose ≥ 25 mg/m2, prior bone marrow transplant, or prior intensive chemotherapy with stem cell support;
3. Presence of any serious concomitant systemic disorders incompatible with the study in the opinion of the investigator (e.g., uncontrolled congestive heart failure, active infection, etc.);
4. Any previous history of another malignancy (other than cured basal cell or squamous cell carcinoma of the skin or cured in-situ carcinoma) within 5 years of study entry;
5. Presence of any significant central nervous system (CNS) or psychiatric disorder(s) that would hamper the patient's compliance;
6. Evidence of peripheral neuropathy grade ≥ 2;
7. Treatment with any other investigational agent or participation in another clinical trial within 28 days prior to study entry;
8. Pregnant or breast-feeding patients or any patient with child-bearing potential not using adequate contraception;
9. Known HIV, HBV, or HCV infection (excluding cured HBV and/or cured HCV infection);
10. Active CNS metastases; however, patients with CNS metastases will be eligible if they have been treated and are stable without symptoms for 4 weeks after completion of treatment, with image documentation required, and must be off steroids;
11. Who require chronic systemic steroid therapy or on any other form of immunosuppressive medication;
12. Has received a live-virus vaccination within 30 days of planned treatment start;
13. With known risk factors for bowel perforation, i.e., history of diverticulitis, intra-abdominal abscess, intestinal obstruction, or abdominal carcinomatosis;
14. Has an active autoimmune disease or a documented history of autoimmune disease;
15. Has a history pneumonitis or interstitial lung disease.
16. Patients who were permanently discontinued from prior immunotherapy due to immune-related adverse events.
17. Patients who are platinum and PD-1/PD-L1 inhibitor double refractory.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: CBP501 (25) + Cisplatin + Nivolumab; CBP501 25mg/m2 and Cisplatin 60mg/m2 will be administered simultaneously. Nivolumab 240mg will be administered following the completion of CBP501 and cisplatin infusions.	Drug: Nivolumab; 240 mg; Other Names: Opdivo; Drug: CBP501 (25); 25 mg/m2; Other Names: CBP501; Drug: Cisplatin; 60mg/m2; Other Names: CDDP
Experimental: Arm 2: CBP501 (16) + Cisplatin + Nivolumab; CBP501 16mg/m2 and Cisplatin 60mg/m2 will be administered simultaneously. Nivolumab 240mg will be administered following the completion of CBP501 and cisplatin infusions.	Drug: Nivolumab; 240 mg; Other Names: Opdivo; Drug: Cisplatin; 60mg/m2; Other Names: CDDP; Drug: CBP501 (16); 16 mg/m2; Other Names: CBP501
Experimental: Arm 3: CBP501 (25) + Cisplatin; CBP501 25mg/m2 and Cisplatin 60mg/m2 will be administered simultaneously.	Drug: CBP501 (25); 25 mg/m2; Other Names: CBP501; Drug: Cisplatin; 60mg/m2; Other Names: CDDP
Experimental: Arm 4: Cisplatin + Nivolumab; Cisplatin 60mg/m2 will be administered as infusion and then Nivolumab 240mg will be administered.	Drug: Nivolumab; 240 mg; Other Names: Opdivo; Drug: Cisplatin; 60mg/m2; Other Names: CDDP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Three-month progression free survival rate (3M PFSR)	Tumor assessment by RECIST v.1.1 criteria will be performed at screening, every 8 weeks starting after Cycle 1 Day 1, at the End-of-Treatment visit, and every 3 months after the End-of-Treatment visit until disease progression is observed.	3 months after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety profiles of the combinations of CBP501, cisplatin, and nivolumab administered once every 21 days	Safety will be assessed throughout the study through clinical and laboratory safety evaluations. These include physical examinations, vital sign measurements, 12-lead ECGs, laboratory safety tests (hematology, INR, serum chemistry, serum cardiac markers), and clinical adverse experience monitoring. Adverse events will be evaluated at each visit throughout the study and assigned a grade, defined by NCI-CTCAE version 5.0 criteria, and relationship to study treatment (unrelated, related).	One year
Progression-free survival (PFS)	Tumor assessment by RECIST v.1.1 criteria will be performed at screening, every 8 weeks starting after Cycle 1 Day 1, at the End-of-Treatment visit, and every 3 months after the End-of-Treatment visit until disease progression is observed.	one year
Confirmed and timepoint objective response rates (cORR/ORR)	Tumor assessment by RECIST v.1.1 criteria will be performed at screening, every 8 weeks starting after Cycle 1 Day 1, at the End-of-Treatment visit, and every 3 months after the End-of-Treatment visit until disease progression is observed.	one year
Duration of responses (DoR)	Tumor assessment by RECIST v.1.1 criteria will be performed at screening, every 8 weeks starting after Cycle 1 Day 1, at the End-of-Treatment visit, and every 3 months after the End-of-Treatment visit until disease progression is observed.	one year
disease control rate (DCR: CR + PR + SD ≥12 weeks)	Tumor assessment by RECIST v.1.1 criteria will be performed at screening, every 8 weeks starting after Cycle 1 Day 1, at the End-of-Treatment visit, and every 3 months after the End-of-Treatment visit until disease progression is observed.	one year
Overall survival (OS)	Tumor assessment by RECIST v.1.1 criteria will be performed at screening, every 8 weeks starting after Cycle 1 Day 1, at the End-of-Treatment visit, and every 3 months after the End-of-Treatment visit until disease progression is observed.	one year

Collaborators and Investigators

• Sponsor: CanBas Co. Ltd.

Publications and helpful links

General Publications

• Sha SK, Sato T, Kobayashi H, Ishigaki M, Yamamoto S, Sato H, Takada A, Nakajyo S, Mochizuki Y, Friedman JM, Cheng FC, Okura T, Kimura R, Kufe DW, Vonhoff DD, Kawabe T. Cell cycle phenotype-based optimization of G2-abrogating peptides yields CBP501 with a unique mechanism of action at the G2 checkpoint. Mol Cancer Ther. 2007 Jan;6(1):147-53. doi: 10.1158/1535-7163.MCT-06-0371.
• Mine N, Yamamoto S, Saito N, Yamazaki S, Suda C, Ishigaki M, Kufe DW, Von Hoff DD, Kawabe T. CBP501-calmodulin binding contributes to sensitizing tumor cells to cisplatin and bleomycin. Mol Cancer Ther. 2011 Oct;10(10):1929-38. doi: 10.1158/1535-7163.MCT-10-1139. Epub 2011 Aug 10.
• Shapiro GI, Tibes R, Gordon MS, Wong BY, Eder JP, Borad MJ, Mendelson DS, Vogelzang NJ, Bastos BR, Weiss GJ, Fernandez C, Sutherland W, Sato H, Pierceall WE, Weaver D, Slough S, Wasserman E, Kufe DW, Von Hoff D, Kawabe T, Sharma S. Phase I studies of CBP501, a G2 checkpoint abrogator, as monotherapy and in combination with cisplatin in patients with advanced solid tumors. Clin Cancer Res. 2011 May 15;17(10):3431-42. doi: 10.1158/1078-0432.CCR-10-2345. Epub 2011 Jan 10.
• Matsumoto Y, Shindo Y, Takakusagi Y, Takakusagi K, Tsukuda S, Kusayanagi T, Sato H, Kawabe T, Sugawara F, Sakaguchi K. Screening of a library of T7 phage-displayed peptides identifies alphaC helix in 14-3-3 protein as a CBP501-binding site. Bioorg Med Chem. 2011 Dec 1;19(23):7049-56. doi: 10.1016/j.bmc.2011.10.004. Epub 2011 Oct 7.
• Mine N, Yamamoto S, Kufe DW, Von Hoff DD, Kawabe T. Activation of Nrf2 pathways correlates with resistance of NSCLC cell lines to CBP501 in vitro. Mol Cancer Ther. 2014 Sep;13(9):2215-25. doi: 10.1158/1535-7163.MCT-13-0808. Epub 2014 Jul 22.
• Krug LM, Wozniak AJ, Kindler HL, Feld R, Koczywas M, Morero JL, Rodriguez CP, Ross HJ, Bauman JE, Orlov SV, Ruckdeschel JC, Mita AC, Fein L, He X, Hall R, Kawabe T, Sharma S. Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma. Lung Cancer. 2014 Sep;85(3):429-34. doi: 10.1016/j.lungcan.2014.06.008. Epub 2014 Jul 5.

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2021
• Primary Completion (Actual): April 14, 2023
• Study Completion (Actual): April 14, 2023

Study Registration Dates

• First Submitted: June 29, 2021
• First Submitted That Met QC Criteria: June 29, 2021
• First Posted (Actual): July 8, 2021

Study Record Updates

• Last Update Posted (Actual): August 15, 2023
• Last Update Submitted That Met QC Criteria: August 14, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Cisplatin; Nivolumab
• Other Study ID Numbers: CBP21-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No