Clinical trial NCT00700336: Study of CBP501 + Pemetrexed + Cisplatin on MPM (Phase I/II)
Official title: Phase I/II Study of a Triplet Combination of CBP501, Pemetrexed and Cisplatin in Patients With Advanced Solid Tumors and in Chemotherapy-naïve Patients With Malignant Pleural Mesothelioma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Malignant Pleural Mesothelioma
Solid Tumors
Keywords: malignant pleural mesothelioma
solid tumors
Lead sponsor: CanBas Co. Ltd.
Sponsor class: INDUSTRY
First posted: 2008-06-18
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The phase I part of the study is a dose-finding study of escalating doses of CBP501 combined with full-dose cisplatin and pemetrexed in patients with histologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective or would otherwise be eligible for cisplatin and pemetrexed as first-line therapy. The maximum tolerated dose (MTD) will be determined based on DLTs occurring during the first treatment cycle. Pharmacokinetics of the triplet combination will be assessed during the phase I part of the trial.

The phase II part will evaluate full-dose cisplatin and pemetrexed combined with CBP501 (at the MTD determined in the phase I part) in previously untreated, unresectable malignant pleural mesothelioma patients. Patients will be randomized in a 2 : 1 ratio to pemetrexed, cisplatin and CBP501 (Arm A) or to pemetrexed and cisplatin (Arm B); randomization will be stratified according to histology and performance status.

Detailed description: This is an open-label, multicenter, international, phase I-II study. The phase I part, a dose-finding study of escalating doses of CBP501 combined with fixed full-dose cisplatin and pemetrexed, has been completed and results are presented in this report. MTD was determined on DLT occurring during the first cycle. This phase I part was evaluated in a patient population with advanced solid tumors The phase II part will evaluate full-dose cisplatin and pemetrexed combined with CBP501 at the MTD determined in the phase I part. Patients will be randomized in a 2:1 ratio to pemetrexed, cisplatin and CBP501 (Arm A) or pemetrexed and cisplatin (Arm B). This phase II part will be evaluated in chemotherapy-naïve patients with malignant pleural mesothelioma

Randomization will be stratified by:

* Histology: epithelial vs other (sarcomatoid or biphasic)
* Performance status: 0-1 vs 2

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent obtained prior to initiation of any study-specific procedures
2. Phase I: Histologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective or would otherwise be eligible for cisplatin and pemetrexed as first-line therapy

   Phase II: Histologically or cytologically confirmed diagnosis of malignant pleural mesothelioma (MPM), not amenable for radical resection, who has not received previous chemotherapy or other systemic treatment
3. Measurable disease according to the modified Response Evaluation Criteria in Solid Tumors (RECIST, see below)
4. Male or female patients aged at least 18 years
5. ECOG Performance Status (PS): 0-2
6. 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)
7. Life expectancy greater than 3 months
8. Adequate organ function
9. 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"
10. 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
11. Ability to cooperate with the treatment and follow-up

Exclusion Criteria:

1. Radiation therapy to more than 30% of the bone marrow prior to entry into the study
2. Phase II only: Mesothelioma originating outside the pleura (e.g.: peritoneum)
3. Absence of measurable lesions
4. The patient has 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.
5. 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)
6. Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient's compliance
7. Evidence of peripheral neuropathy \> grade 1 according to NCI-CTCAE Version 3
8. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to study entry
9. Pregnant or breast-feeding patients or any patient with childbearing potential not using adequate contraception
10. Known HIV, HBV, HCV infection
11. Presence of CNS metastases

Primary outcomes:
measure: 4M PFS Rate of Patients With Previously Untreated, Unresectable Malignant Pleural Mesothelioma (MPM) Treated With CBP501, Pemetrexed and Cisplatin
timeFrame: End of study
Secondary outcomes:
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Tucson
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Detroit
country: United States
facility: Karmanos Cancer Institute/Wayne State University
state: Michigan
city: Las Vegas
country: United States
facility: Nevada Cancer Institute
state: Nevada
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: New York
country: United States
facility: Memorial-Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Ctr.
state: Pennsylvania
city: San Antonio
country: United States
facility: Cancer Therapy & Research Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Lee Krug
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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. doi: 10.1158/1535-7163.MCT-06-0371.
citation: 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. doi: 10.1158/1535-7163.MCT-10-1139. Epub 2011 Aug 10.
citation: 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. doi: 10.1158/1078-0432.CCR-10-2345. Epub 2011 Jan 10.
citation: 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 Dec 1;19(23):7049-56. doi: 10.1016/j.bmc.2011.10.004. Epub 2011 Oct 7.