Triplet Combination First Line Treatment in Non Small Cell Lung Cancer (NSCLC)

This is a randomized, open-label, multicenter, phase II study to compare a triplet combination of CBP501, pemetrexed and cisplatin with pemetrexed/cisplatin when administered to patients with locally advanced (stage IIIB with malignant pleural effusion or pericardial effusion) or metastatic (stage IV) non-squamous NSCLC as consecutive i.v. infusions according to a once-every-3-weeks schedule.

The protocol will evaluate full-dose cisplatin and pemetrexed with or without CBP501. Patients will be randomized in a 1:1 ratio to pemetrexed, cisplatin and CBP501 (Arm A) or pemetrexed and cisplatin (Arm B). Randomization will be stratified according to whether or not patients are eligible for bevacizumab therapy.

Preclinical and clinical findings that support this protocol are:

* CBP501 has exhibited interesting preclinical activity in various lung cancer cell lines.
* Synergism was documented with CBP501/cisplatin in the preclinical studies with lung cancer cell lines.
* The dose-limiting toxicity (DLT) of CBP501 was rapid onset allergic reaction, as was suggested by preclinical toxicology. Other toxicities were quite limited. No evidence of potentiation of either CBP501 or cisplatin toxicity was found in the combination phase I trial, and the toxicity of the combination, primarily related to cisplatin, is manageable. It is expected that CBP501 and pemetrexed will display non-overlapping toxicity profiles in combination, given that hematological toxicity and gastrointestinal toxicity are the principal toxicity types of the latter.
* Given the acceptable safety of the cisplatin/ pemetrexed combination, it is anticipated that the addition of CBP501 to this combination can be evaluated without excessive risk in the phase II programs.
* The phase I study of CBP501 in combination with pemetrexed/cisplatin (phase I part of the mesothelioma program) did not show DLTs or evidence of enhancement of toxicities with the triplet combination. The RD of CBP501 25 mg/m², cisplatin 75 mg/m² and pemetrexed 500 mg/m² is currently in use in the phase II study with first line mesothelioma patients.
* Hints of activity were observed during the phase I study with CBP501 and cisplatin.
* No pharmacokinetics (PK) interaction was documented between cisplatin and CBP501.

This is a randomized, open-label, multicenter, phase II study to compare a triplet combination of CBP501, pemetrexed and cisplatin with pemetrexed/cisplatin when administered to patients with locally advanced (stage IIIB with malignant pleural effusion or pericardial effusion) or metastatic (stage IV) non-squamous NSCLC as consecutive i.v. infusions according to a once-every-3-weeks schedule.

The protocol will evaluate full-dose cisplatin and pemetrexed with or without CBP501. Patients will be randomized in a 1:1 ratio to pemetrexed, cisplatin and CBP501 (Arm A) or pemetrexed and cisplatin (Arm B). Randomization will be stratified according to whether or not patients are eligible for bevacizumab therapy.

The combination of cisplatin/pemetrexed has come to be recognized as the new standard of care for patients with untreated, unresectable malignant pleural mesothelioma (MPM) and untreated NSCLC non-squamous cell histology.

Preclinical and clinical findings that support this protocol are:

* CBP501 has exhibited interesting preclinical activity in various lung cancer cell lines.
* Synergism was documented with CBP501/cisplatin in the preclinical studies with lung cancer cell lines.
* The dose-limiting toxicity (DLT) of CBP501 was rapid onset allergic reaction, as was suggested by preclinical toxicology. Other toxicities were quite limited. No evidence of potentiation of either CBP501 or cisplatin toxicity was found in the combination phase I trial, and the toxicity of the combination, primarily related to cisplatin, is manageable. It is expected that CBP501 and pemetrexed will display non-overlapping toxicity profiles in combination, given that hematological toxicity and gastrointestinal toxicity are the principal toxicity types of the latter.
* Given the acceptable safety of the cisplatin/ pemetrexed combination, it is anticipated that the addition of CBP501 to this combination can be evaluated without excessive risk in the phase II programs.
* The phase I study of CBP501 in combination with pemetrexed/cisplatin (phase I part of the mesothelioma program) did not show DLTs or evidence of enhancement of toxicities with the triplet combination. The RD of CBP501 25 mg/m², cisplatin 75 mg/m² and pemetrexed 500 mg/m² is currently in use in the phase II study with first line mesothelioma patients.
* Hints of activity were observed during the phase I study with CBP501 and cisplatin.
* No pharmacokinetics (PK) interaction was documented between cisplatin and CBP501.

Eligibility Criteria:
Inclusion Criteria:

* Signed informed consent obtained prior to initiation of any study-specific procedures
* Histologically or cytologically confirmed diagnosis of non-squamous non small cell lung cancer (NSCLC), not amenable for radical resection, stage IIIB with pleural or pericardial effusion or stage IV, who has not received previous chemotherapy or other systemic treatment
* At least one unidimensionally measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST)
* Male or female patients aged at least 18 years
* ECOG Performance Status (PS): 0-1
* Life expectancy \> 3 months
* Prior local radiotherapy is allowed if it was completed ≥ 3 weeks prior to the first dose of the study medication
* Concomitant palliative radiotherapy to an existing bone lesion for pain control is allowed
* Prior surgery is allowed if it is performed at least 4 weeks prior to the first dose of study medication and patient should be fully recovered
* Adequate organ function, including the following:
* Bone marrow: white blood cell (WBC) count \>= 4 x 109/L, absolute neutrophil count (ANC) \>= 1.5 x 109/L, platelet count \>= 100 x 109/L, hemoglobin \>= 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, albumin \>= 3.0 g/dL
* Renal: Serum creatinine ≤ 1.5 mg/dL or creatinine clearance \>= 45 mL/min (calculated according to the Cockroft and Gault formula)
* Female patients of child-bearing potential must have a negative pregnancy test and be using 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 cooperate with the treatment and follow-up

Exclusion Criteria:

* Radiation therapy to more than 30% of the bone marrow prior to entry into the study
* Histology of pure bronchioloalveolar carcinoma or neuroendocrine features in the tumor sample
* Previous treatment with chemotherapy, new biological therapies (small molecules, antibodies), immunotherapy
* Absence of measurable lesions
* An ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled medical disorders in the opinion of the Investigator
* Any previous history of another malignancy within 5 years of study entry (other than cured basal cell carcinoma of the skin or cured in-situ carcinoma of the cervix)
* Presence of any significant central nervous system (CNS) 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
* Presence of symptomatic brain metastasis. Patients with brain metastases must:
* Have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks after completion of the definitive therapy.
* Be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs
* Inability or unwillingness to take folic acid, vitamin B12 or corticosteroids
* Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents, other than aspirin dose ≤ 1.3 grams per day, for a 5-day period (8-day period for long-acting agents, such piroxicam)
* Significant weight loss (\>= 10% body weight during preceding 6 weeks)
* Presence of clinically significant (by physical exam) third space fluid collections, e.g., ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry