Pemetrexed Disodium and Cisplatin With or Without Cediranib Maleate in Treating Patients With Malignant Pleural Mesothelioma

Primary Outcome Measures:

• Overall survival and safety/toxicity of Vorinostat in this population. Treatment will continue until disease progression or unacceptable toxicity. [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

• Progression-free survival, Overall objective response rate, dyspnea score on LCSS-Meso scale, and Forced Vital Capacity change. Treatment will continue until disease progression or unacceptable toxicity. [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Detailed Description

Objectives:

• To establish the maximum tolerated dose and the recommended phase II dose of cediranib maleate in combination with pemetrexed disodium and cisplatin in patients with malignant pleural mesothelioma. (Phase I)
• To compare the progression-free survival of patients treated with pemetrexed disodium and cisplatin with vs without cediranib maleate. (Phase II)
• To compare the overall survival of patients treated with these regimens. (Phase II)
• To assess the safety and toxicity profile of these regimens.
• To assess the response rate (confirmed and unconfirmed, complete and partial responses) and disease control rate (responsive or stable disease) using RECIST criteria and modified RECIST criteria for pleural tumors in a subset of patients with measurable disease. (Phase II)
• To assess the rate of agreement between local and central pathology review of mesothelioma and its histologic subtypes. (Phase II)
• To collect specimens for banking for use in future research studies. (Phase II)

Outline: This is a multicenter, phase I dose-escalation study of cediranib maleate followed by a phase II randomized study. Patients enrolled in the phase II portion of the study are stratified according to Zubrod performance status (0-1 vs 2) and histologic subtype (epithelioid vs biphasic/sarcomatoid).

• Phase I: Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1 and oral cediranib maleate once daily on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive oral cediranib maleate alone once daily in the absence of disease progression or unacceptable toxicity.
• Phase II: Patients are randomized to 1 of 2 treatment arms.
  • Arm I: Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1 and oral cediranib maleate once daily at the maximum tolerated dose determined in phase I on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive oral cediranib maleate alone once daily in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive pemetrexed disodium and cisplatin as in arm I and oral placebo once daily on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive oral placebo alone once daily in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for up to 3 years.

Criteria

Disease Characteristics

• Histologically confirmed malignant pleural mesothelioma
  • Not planning to undergo surgical resection
• Measurable or non-measurable disease by RECIST or modified RECIST criteria for pleural tumors as documented by CT scan

Patient Characteristics

• Zubrod performance status 0-2
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9.0 g/dL (transfusion allowed)
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGOT or SGPT ≤ 2.5 times ULN (≤ 5 times ULN if liver metastases are present)
• Serum creatinine ≤ 1.5 times ULN
• Creatinine clearance ≥ 60 mL/min
• Proteinuria ≤ +1 on 2 consecutive dipsticks taken ≥ 7 days apart
  • Repeat urinalysis not required provided first urinalysis shows no protein
• Not pregnant or nursing
• Fertile patients must agree to use effective contraception
• Must be able to swallow oral medications
• No mean QTc > 500 msec (with Bazett correction) by ECG or other significant ECG abnormality
• No NYHA class III-IV congestive heart failure
• No clinically significant hemoptysis, defined as > 1 tablespoon of bright red blood, within the past year
• No known HIV infection
• No other malignancy within the past 5 years except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or adequately treated stage I or II cancer from which the patient is currently in complete remission

Prior Concurrent Therapy

• See Disease Characteristics
• No prior systemic therapy (chemotherapy or other biological therapy) for unresectable malignant pleural mesothelioma
  • Prior systemic chemotherapy or biologic therapy as neoadjuvant or adjuvant therapy allowed provided disease has recurred and systemic therapy was completed > 6 months before study entry
• No prior therapy with any of the study drugs
• At least 28 days since prior surgery (e.g., pleurectomy, pleurodeses, thoracic or other major surgeries) and recovered
• At least 28 days since prior radiotherapy and recovered
• No concurrent medication that may markedly affect renal function (e.g., vancomycin, amphotericin, pentamidine)
• No concurrent drugs or biologics with proarrhythmic potential
• No concurrent major surgery
• No other concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy or any other type of therapy for treatment of cancer