Triplet Combination First Line Treatment in Non Small Cell Lung Cancer (NSCLC) - Full Text View

Sponsor:	CanBas Co. Ltd.
Information provided by (Responsible Party):	CanBas Co. Ltd.
ClinicalTrials.gov Identifier:	NCT00942825

Purpose

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.

Condition	Intervention	Phase
Metastatic Non-squamous Non Small Cell Lung Cancer	Drug: CBP501 + Cisplatin + Pemetrexed Drug: Cisplatin + Pemetrexed	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase II Study of a Triplet Combination of CBP501, Pemetrexed and Cisplatin as First Line Treatment in Patients With Locally Advanced (Stage IIIB With Malignant Pleural Effusion or Pericardial Effusion) or Metastatic (Stage IV) Non-squamous Non Small Cell Lung Cancer (NSCLC)

Resource links provided by NLM:

MedlinePlus related topics: Cancer Lung Cancer Pericardial Disorders

Drug Information available for: Cisplatin Pemetrexed Pemetrexed disodium CBP501

U.S. FDA Resources

Further study details as provided by CanBas Co. Ltd.:

Primary Outcome Measures:

The primary efficacy endpoint is Progression free survival, analyzed in the treated population. PFS is assessed from randomization until either tumor progression, as per RECIST criteria, or until death due to any reason. [ Designated as safety issue: No ]

Secondary Outcome Measures:

Objective response rate (CR + PR): response is to be assessed according to RECIST criteria (see Section 7.1), with responses to be confirmed at least 4 weeks after the first observation of response. [ Designated as safety issue: No ]
Duration of response is assessed in patients with confirmed response, from the first documentation of response until the first occurrence of disease progression. In case of death due to reasons other than disease progression, patie [ Designated as safety issue: No ]
Rate of tumor growth control (TGC): patients with tumor growth control are those patients who experience confirmed response (CR or PR) or stable disease lasting at least 12 weeks. [ Designated as safety issue: No ]
Duration of tumor growth control: duration of TGC is assessed from randomization to the first occurrence of disease progression or death in patients with confirmed TGC. [ Designated as safety issue: No ]
Overall survival: OS is assessed from randomization until the date of death from any cause. [ Designated as safety issue: No ]
Incidence and severity of adverse events and laboratory abnormalities, graded according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 3.0 [ Designated as safety issue: Yes ]
Occurrence of Serious Adverse Events. [ Designated as safety issue: Yes ]
Occurrence of treatment discontinuation due to adverse events. [ Designated as safety issue: Yes ]

Estimated Enrollment:	192
Study Start Date:	April 2009
Estimated Study Completion Date:	November 2012
Estimated Primary Completion Date:	June 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: A CBP501 +Cisplatin + Pemetrexed CBP501 25 mg/m2 + Cisplatin 75 mg/m2 + Pemetrexed 500mg/m2	Drug: CBP501 + Cisplatin + Pemetrexed 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.
Active Comparator: B Cisplatin + Pemetrexed Cisplatin + Pemetrexed	Drug: Cisplatin + Pemetrexed 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.

Arms

Assigned Interventions

Experimental: A CBP501 +Cisplatin + Pemetrexed

CBP501 25 mg/m2 + Cisplatin 75 mg/m2 + Pemetrexed 500mg/m2

Drug: CBP501 + Cisplatin + Pemetrexed

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.

Active Comparator: B Cisplatin + Pemetrexed

Cisplatin + Pemetrexed

Drug: Cisplatin + Pemetrexed

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00942825

Locations

United States, Nevada
Nevada Cancer Institute
Las Vegas, Nevada, United States, 89135
United States, Pennsylvania
Penn State Cancer Institute
Hershey, Pennsylvania, United States, 17033
United States, Texas
Mary Crowley Cancer Research Centers
Dallas, Texas, United States, 75246

Sponsors and Collaborators

CanBas Co. Ltd.

More Information

Publications:

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. Epub 2011 Jan 10.

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. Epub 2011 Aug 10.

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.

Suganuma M, Kawabe T, Hori H, Funabiki T, Okamoto T. Sensitization of cancer cells to DNA damage-induced cell death by specific cell cycle G2 checkpoint abrogation. Cancer Res. 1999 Dec 1;59(23):5887-91.

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 Oct 7; [Epub ahead of print]

Responsible Party:	CanBas Co. Ltd.
ClinicalTrials.gov Identifier:	NCT00942825 History of Changes
Other Study ID Numbers:	CBP08-02
Study First Received:	July 17, 2009
Last Updated:	October 31, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by CanBas Co. Ltd.:

NSCL
non-squamous non small cell lung cancer
Lung Cancer
Lung
non-squamous

metastatic
pleural effusion
Stage IIIb
Stage IV
NSCLC

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Pericardial Effusion
Pleural Effusion
Pleural Effusion, Malignant
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Heart Diseases
Cardiovascular Diseases

Pleural Diseases
Pleural Neoplasms
Pemetrexed
Cisplatin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on February 21, 2012