Clinical trial NCT04953962: Study of CBP501/Cisplatin/Nivolumab Combinations in Advanced Pancreatic Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pancreatic Cancer Stage IV
Lead sponsor: CanBas Co. Ltd.
Sponsor class: INDUSTRY
First posted: 2021-07-08
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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%.

Eligibility criteria: 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.

Primary outcomes:
measure: Three-month progression free survival rate (3M PFSR)
timeFrame: 3 months after treatment
Secondary outcomes:
measure: Safety profiles of the combinations of CBP501, cisplatin, and nivolumab administered once every 21 days
timeFrame: One year
measure: Progression-free survival (PFS)
timeFrame: one year
measure: Confirmed and timepoint objective response rates (cORR/ORR)
timeFrame: one year
measure: Duration of responses (DoR)
timeFrame: one year
measure: disease control rate (DCR: CR + PR + SD ≥12 weeks)
timeFrame: one year
measure: Overall survival (OS)
timeFrame: one year
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Oncology Associates, PC-HOPE
state: Arizona
city: Los Angeles
country: United States
facility: Ochsner Clinic Foundation
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Newark
country: United States
facility: Medical Oncology Hematology Consultants, PA
state: Delaware
city: Arlington Heights
country: United States
facility: Illinois Cancer Specialists
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan hospital
state: Michigan
city: Minneapolis
country: United States
facility: Minnesota oncology Hematology, P.A.
state: Minnesota
city: Henderson
country: United States
facility: James D Sanchez
state: Nevada
city: Cincinnati
country: United States
facility: Oncology Hematology Care, Inc.
state: Ohio
city: Austin
country: United States
facility: Texas Oncology-Austin Midtown
state: Texas
city: Dallas
country: United States
facility: Mary Crowley Medical Research Center
state: Texas
city: Dallas
country: United States
facility: Texas Oncology-Baylor Charles A. Sammons Cancer Center
state: Texas
city: McAllen
country: United States
facility: Texas Oncology-McAllen South Second Street
state: Texas
city: McKinney
country: United States
facility: Texas Oncology- McKinney
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology-San Antonio Northeast
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Medical Center
state: Texas
city: Tyler
country: United States
facility: Texas Oncology-Northeast Texas
state: Texas
city: Arrington
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Washington
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.