Triplet Combination First Line Treatment in Non Small Cell Lung Cancer (NSCLC)
Condition: Metastatic Non-squamous Non Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: CBP501 + Cisplatin + Pemetrexed; Cisplatin + Pemetrexed
Intervention description: CBP501, pemetrexed and cisplatin will be administered on the same day (Day 1), every 3 weeks for a maximum of six cycles. A cycle is considered to be 3 weeks (21 days).
CBP501 25 mg/m² will be administered as an i.v. infusion of 1 hour.
Pemetrexed 500 mg/m² will be administered as an i.v. infusion over 10 minutes, immediately after the CBP501 infusion.
Cisplatin 75 mg/m² will be administered as a 1-hour i.v. infusion immediately after the pemetrexed infusion.; Pemetrexed and cisplatin will be administered on the same day (Day 1), every 3 weeks for a maximum of six cycles. A cycle is considered to be 3 weeks (21 days).
Pemetrexed 500 mg/m² will be administered as an i.v. infusion over 10 minutes.
Cisplatin 75 mg/m² will be administered as a 1-hour i.v. infusion immediately after the pemetrexed infusion.
Intervention MeSH terms: Cisplatin; Pemetrexed
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 195.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: NSCL; non-squamous non small cell lung cancer; Lung Cancer; Lung; non-squamous; metastatic; pleural effusion; Stage IIIb; Stage IV; NSCLC

Summary:

      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.
    

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