Phase I Study of CBP501 and Cisplatin in Patients With Advanced Refractory Solid Tumors

9.1 23BOverall Study Design and Plan This was an open-label, multicenter, dose-escalation and pharmacokinetic Phase I study of CBP501 and cisplatin administered as consecutive IV infusions according to a once-every-3-weeks schedule in patients with advanced solid tumors refractory to standard therapy. The study was conducted in three US centers. During the course of the study, an amendment was introduced (#3, October 17th, 2007; see section X9.8X) to allow administration of a unique dosing of single agent CBP501 prior to the initiation of combination therapy to enable completion of the pharmacokinetic (PK) characterization of single agent CBP501. Pharmacodynamic analysis involving phosphoserine 216 evaluations was also removed. See section X16.1.1X for copies of the protocol and all protocol amendments. With 8 additional patients included at the recommended dose (at DL6), it was decided to stop all PK and CTC sampling (and therefore the day-7 CBP501 alone infusion), as sufficient information had been retrieved. In addition, based on evidence of efficacy observed in ovarian cancer patients, a further 10 ovarian and 4 endometrial cancer patients were to be included at the recommended dose; these patients were to be assessed for DLT to confirm the identification of the MTD.

Case Report Forms were used to collect the data, and data management was carried out by AAIOncology. All laboratory data and Investigator observations were be transcribed into the CRF. ECG, U/S, MRI and CT scans were to be reported in summary in the CRF. The original reports, traces and films were to be retained by the Investigators for future reference. See section X16.1.2X for a sample CRF.

Inclusion criteria

• Signed informed consent obtained prior to initiation of any study-specific procedures.
• Pathologically-confirmed, locally advanced or metastatic solid tumors, refractory to standard therapy.
• Male or female patients aged 18 years or over.
• ECOG Performance Status (PS): 0-1.
• Life expectancy > 3 months.
• Previous anticancer treatment must be discontinued at least 3 weeks prior to first dose of study treatment (6 weeks for mitomycin C; 6 weeks for anti-androgen therapy if discontinued prior to treatment initiation, with the exception of 8 weeks for bicalutamide).
• Adequate organ function including the following:
• Bone Marrow: absolute neutrophil count (ANC) ³ 1.5 x 109/L, platelet count ³ 100 x 109/L, hemoglobin ³ 9 g/dL
• Hepatic: Bilirubin £ 1.5 x the upper limit of normal (ULN), aspartate transaminases (AST/SGOT) and alanine transaminases (ALT/SGPT) £ 2.5 x ULN (or ≤ 5 x ULN if liver metastases are present), INR £ 1.5 x ULN
• Renal: Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ³ 70 mL/min (calculated according to the Cockroft and Gault formula)
• Metabolic: serum potassium, calcium and magnesium ³ lower limit of normal (LLN)
• Creatine phosphokinase isoenzymes: CPK-MB, CPK-MM ≤ ULN
• Troponin I serum level within normal values
• Female patients of child-bearing potential must have a negative pregnancy test and use at least one form of contraception as approved by the investigator for 4 weeks prior to the study and 4 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 one year or are surgically sterile".
• Male patients must use a form of barrier contraception approved by the investigator during the study and for 4 months after the last dose of study drug.
• Ability to co-operate with the treatment and follow-up.

Exclusion criteria

• Radiation therapy to more than 30% of the bone marrow prior to entry into the study.
• Prior chemotherapy with nitrosoureas or high dose carboplatin (AUC > 6 mg/mL), prior mitomycin C cumulative dose ³ 25 mg/m², prior bone marrow transplant or intensive chemotherapy with stem cell support.
• Presence of any serious concomitant systemic disorders incompatible with the study (e.g. uncontrolled congestive heart failure, active infection, etc.).
• Any previous history of another malignancy (other than cured basal cell carcinoma of the skin or cured in-situ carcinoma of the cervix) within 5 years of study entry.
• Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient's compliance.
• Evidence of peripheral neuropathy > grade 1 according to NCI-CTCAE Version 3.
• 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 childbearing potential not using adequate contraception.
• Known HIV, HBV, HCV infection.
• Active CNS metastasis: patients with a history of 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 either off steroids or on a stable dose of steroids for > 1 week prior to enrollment.