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

Study Overview
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Brief Summary
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This randomized phase I/II trial is studying the side effects and best dose of cediranib maleate when given together with pemetrexed disodium and cisplatin and to see how well it works in treating patients with malignant pleural mesothelioma. Drugs used in chemotherapy, pemetrexed disodium and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving pemetrexed disodium and cisplatin together with cediranib maleate may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To establish the maximum tolerated dose (MTD) and the recommended phase II dose of cediranib maleate (cediranib) in combination with cisplatin and pemetrexed disodium (pemetrexed). (Phase I) II. To assess the safety and toxicity of the regimen. (Phase I) III. To assess whether cisplatin/pemetrexed plus cediranib as compared to cisplatin/pemetrexed plus placebo improves progression-free survival in patients with malignant pleural mesothelioma. (Phase II) IV. To compare overall survival in patients treated with cisplatin/pemetrexed plus cediranib to those treated with cisplatin/pemetrexed plus placebo. (Phase II) V. To assess the safety and toxicity profile of the regimen. (Phase II) VI. To assess response rate (confirmed and unconfirmed, complete and partial responses) and disease control rate (response or stable disease) in the subset of patients with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. (Phase II) VII. To assess response rate and disease control rate using modified RECIST criteria for pleural tumors in the subset of patients with measurable disease by modified RECIST criteria for pleural tumors. (Phase II) VIII. To assess the rate of agreement between local and central pathology review of mesothelioma and its histologic subtypes. (Phase II) IX. To collect specimens for banking for use in future research studies. (Phase II) OUTLINE: This is a phase I dose-escalation study of cediranib maleate followed by a phase II study. PHASE I (CLOSED): Patients receive pemetrexed disodium intravenously (IV) over 10 minutes and cisplatin IV over 2 hours on day 1 and cediranib maleate orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cediranib maleate alone PO QD 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 cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cediranib maleate alone PO QD in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive pemetrexed disodium and cisplatin as in arm I and placebo PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive placebo alone PO QD in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 2 years and then at 3 years.

Official Title
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A Phase I/Randomized Phase II Study of Cediranib (NSC#732208) Versus Placebo in Combination With Cisplatin and Pemetrexed in Chemonaive Patients With Malignant Pleural Mesothelioma

Conditions
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Epithelioid Mesothelioma, Pleural Malignant Mesothelioma, Recurrent Malignant Mesothelioma, Sarcomatoid Mesothelioma

Intervention / Treatment
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* Drug: Cediranib Maleate
* Drug: Cisplatin
* Other: Laboratory Biomarker Analysis
* Drug: Pemetrexed Disodium
* Other: Placebo Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have histologically or cytologically confirmed diagnosis of malignant pleural mesothelioma; surgical resection must not be planned Patients must have measurable or non-measurable disease by both RECIST and modified RECIST criteria for pleural tumors as documented by computed tomography (CT) scan; examinations for assessment of measurable disease must have been completed within 28 days prior to registration; examinations for assessment of non-measurable disease must have been performed within 42 days prior to registration; all disease must be assessed and documented on the RECIST 1.1 and Modified RECIST Baseline Tumor Assessment Form Patients must not have received any prior systemic therapy (chemotherapy or other biologic therapy) for their unresectable malignant pleural mesothelioma; prior systemic chemotherapy or biologic therapy is allowed as neoadjuvant or adjuvant treatment, disease has now recurred, and all systemic treatment was completed > 6 months prior registration; prior therapy must not have included cediranib Patients may have received prior surgery (e.g., pleurectomy, pleurodeisis) provided at least 28 days have elapsed since surgery (thoracic or other major surgeries) and patients have recovered from all associated toxicities at the time of registration; there must be no anticipated need for major surgical procedures during protocol treatment Patients may have received prior radiation therapy provided at least 28 days have elapsed since the last treatment and patients have recovered from all associated toxicities at the time of registration Institutions must seek additional patient consent for the banking and future use of specimens Patient must have Zubrod performance status 0-2 Absolute neutrophil count >= 1,500 mcl Platelets >= 100,000/ml Hemoglobin >= 9.0 g/dl (may be reached by transfusion) Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN (if liver metastases are present, SGOT or SGPT must be =< 5.0 x IULN) Serum creatinine =< 1.5 x IULN Calculated creatinine clearance >= 60 mL/min Urine protein must be screened by urine analysis within 28 days prior to registration; patient must not have greater than +1 proteinuria on two consecutive dipsticks taken no less than 7 days apart; however, if the first urinalysis shows no protein, then a repeat urinalysis is not required Patient must have an electrocardiogram (ECG) performed within 42 days prior to registration; patient must not have mean corrected QT (QTc) > 500 msec (with Bazett's correction) in screening electrocardiogram, or other significant ECG abnormality, New York Heart Association (NYHA) classification III or IV; patient must not require concurrent use of drugs or biologics with proarrhythmic potential Patient must not be receiving any medication that may markedly affect renal function (e.g., vancomycin, amphotericin, pentamidine) Patient must not have had clinically significant hemoptysis, defined as greater than 1 tablespoon of bright red blood, within one year prior to registration; although hemoptysis has not been associated with cediranib, it may be a class effect for anti-angiogenic agents and therefore a risk factor for this experimental agent Patient must be able to swallow oral medications Patients must not have known human immunodeficiency virus (HIV) infection Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures Patient must have no plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy or any other type of therapy for treatment of cancer while on this protocol treatment No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (pemetrexed disodium, cisplatin, cediranib maleate))<br>Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1 and cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cediranib maleate alone PO QD in the absence of disease progression or unacceptable toxicity. | Drug: Cediranib Maleate<br>* Given orally<br>* Other names: Recentin;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;|
| Active Comparator: Arm II (pemetrexed disodium, cisplatin, placebo)<br>Patients receive pemetrexed disodium and cisplatin as in arm I and placebo PO QD on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive placebo alone PO QD in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;Other: Placebo Administration<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Cediranib in Combination With Cisplatin and Pemetrexed (Phase I) | MTD was determined by testing dose-de-escalation to 20mg PO daily on dose de-escalation cohort 1 to 2 with 3 to 6 patients each. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in > 33% of participants. Toxicities will be graded according to the CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events. Dose-limiting toxicities (DLT) apply only during Cycle 1 and must be drug-related (i.e. possibly, probably or definitely related to one of the 3 study drugs). The following events occurring in the first cycle of treatment are considered dose limiting. Febrile neutropenia Grade 4 neutrophil count decrease for more than 7 days' duration Grade 4 platelet count decrease Grade 3 or 4 non-hematologic toxicity (excluding alopecia) | Weekly during first cycle (1cycle = 21 days). Then will be reported every cycle while patient is on treatment. | 
| Progression-free Survival (Phase II) | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v 1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesions, or the appearance of new lesions. | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, whichever came first, assessed up to 5 years.Disease assessment will be repeated every 6 weeks until disease progression. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Phase II) | From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact. | From date of registration to death.Disease assessment will be repeated every 6 weeks until disease progression. After progression, follow up will occur every 6 months for the first two years and then at the end of the third year after registration. | 
| Response Rate by RECIST1.1 (Phase II) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. All target measurable lesions must be assessed using the same techniques as baseline. | Disease assessment will be repeated every 6 weeks until disease progression, up to 3 years. Best response is documented for as long as the patient remains on protocol treatment. | 
| Disease Control Rate by RECIST 1.1 (Phase II) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (STA): Does not qualify for CR, PR, Progression or Symptomatic Deterioration. Disease Control Rate (DCR) = CR + PR + STA All target measurable lesions must be assessed using the same techniques as baseline. | Disease assessment will be repeated every 6 weeks until disease progression, up to 3 years.Disease control rate is documented for as long as the patient remains on protocol treatment. | 
| Response Rate by Modified RECIST (Phase II) | Per modified RECIST for Pleural Tumors. In addition to RECIST1.1, for modified RECIST, measurements based on the sum of 6 CT cuts in the pleural perpendicular to the chest wall are applied to standard RECIST criterial (sum of 6 = one univariate diameter). Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. All target measurable lesions must be assessed using the same techniques as baseline. | Disease assessment will be repeated every 6 weeks until disease progression, up to 3 years.Best response is documented for as long as the patient remains on protocol treatment. | 
| Disease Control Rate by Modified RECIST (Phase II) | Per modified RECIST for Pleural Tumors. In addition to RECIST1.1, for modified RECIST, measurements based on the sum of 6 CT cuts in the pleural perpendicular to the chest wall are applied to standard RECIST criterial (sum of 6 = one univariate diameter). Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (STA), does not qualify for CR, PR, Progression or Symptomatic Deterioration. Disease Control Rate (DCR) = CR + PR + STA. All target measurable lesions must be assessed using the same techniques as baseline. | Disease assessment will be repeated every 6 weeks until disease progression, up to 3 years.Disease control is documented for as long as the patient remains on protocol treatment. | 
| (Phase I) Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Toxicity assessment is repeated weekly during first cycle (1cycle = 21 days), then every cycle while patient is on treatment. | 
| (Phase II) Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Toxicity assessment is repeated every 3 weeks while patient is on treatment. |