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

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):

• CBP501 25 mg/m2 + cisplatin 60 mg/m2 + nivolumab 240 mg
• CBP501 16 mg/m2 + cisplatin 60 mg/m2 + nivolumab 240 mg
• CBP501 25 mg/m2 + cisplatin 60 mg/m2
• 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%.

Inclusion criteria

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

• Male or female patients aged ≥ 18 years at time of informed consent;
• ECOG Performance Status (PS) 0-1;
• Life expectancy > 3 months;
• 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);
• 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);
• 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;
• 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.
• Ability to cooperate with study treatment and follow-up.

Exclusion criteria

• Radiation therapy to >30% of bone marrow prior to study entry;
• Prior chemotherapy with nitrosoureas, prior mitomycin C cumulative dose ≥ 25 mg/m2, prior bone marrow transplant, or prior intensive chemotherapy with stem cell support;
• 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.);
• 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;
• Presence of any significant central nervous system (CNS) or psychiatric disorder(s) that would hamper the patient's compliance;
• Evidence of peripheral neuropathy grade ≥ 2;
• Treatment with any other investigational agent or participation in another clinical trial within 28 days prior to study entry;
• Pregnant or breast-feeding patients or any patient with child-bearing potential not using adequate contraception;
• Known HIV, HBV, or HCV infection (excluding cured HBV and/or cured HCV infection);
• 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;
• Who require chronic systemic steroid therapy or on any other form of immunosuppressive medication;
• Has received a live-virus vaccination within 30 days of planned treatment start;
• With known risk factors for bowel perforation, i.e., history of diverticulitis, intra-abdominal abscess, intestinal obstruction, or abdominal carcinomatosis;
• Has an active autoimmune disease or a documented history of autoimmune disease;
• Has a history pneumonitis or interstitial lung disease.
• Patients who were permanently discontinued from prior immunotherapy due to immune-related adverse events.
• Patients who are platinum and PD-1/PD-L1 inhibitor double refractory.