Pemetrexed Disodium and Cisplatin With or Without Cediranib Maleate in Treating Patients With Malignant Pleural Mesothelioma
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| ClinicalTrials.gov Identifier: NCT01064648 |
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Recruitment Status :
Active, not recruiting
First Posted : February 8, 2010
Results First Posted : February 5, 2020
Last Update Posted : September 21, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Epithelioid Mesothelioma Pleural Malignant Mesothelioma Recurrent Malignant Mesothelioma Sarcomatoid Mesothelioma | Drug: Cediranib Maleate Drug: Cisplatin Other: Laboratory Biomarker Analysis Drug: Pemetrexed Disodium Other: Placebo Administration | Phase 1 Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 117 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | March 15, 2010 |
| Actual Primary Completion Date : | June 1, 2018 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (pemetrexed disodium, cisplatin, cediranib maleate))
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.
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Drug: Cediranib Maleate
Given orally
Other Names:
Drug: Cisplatin Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Pemetrexed Disodium Given IV
Other Names:
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Active Comparator: Arm II (pemetrexed disodium, cisplatin, placebo)
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.
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Drug: Cisplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Pemetrexed Disodium Given IV
Other Names:
Other: Placebo Administration Given orally |
- Maximum Tolerated Dose of Cediranib in Combination With Cisplatin and Pemetrexed (Phase I) [ Time Frame: Weekly during first cycle (1cycle = 21 days). Then will be reported every cycle while patient is on treatment. ]
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)
- Progression-free Survival (Phase II) [ Time Frame: 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. ]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.
- Overall Survival (Phase II) [ Time Frame: 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. ]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.
- Response Rate by RECIST1.1 (Phase II) [ Time Frame: 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. ]
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 Control Rate by RECIST 1.1 (Phase II) [ Time Frame: 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. ]
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.
- Response Rate by Modified RECIST (Phase II) [ Time Frame: 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. ]
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 Control Rate by Modified RECIST (Phase II) [ Time Frame: 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. ]
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.
- (Phase I) Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Toxicity assessment is repeated weekly during first cycle (1cycle = 21 days), then every cycle while patient is on treatment. ]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.
- (Phase II) Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Toxicity assessment is repeated every 3 weeks while patient is on treatment. ]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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01064648
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| Principal Investigator: | Anne S Tsao | Southwest Oncology Group |
Documents provided by National Cancer Institute (NCI):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01064648 |
| Other Study ID Numbers: |
NCI-2011-02015 NCI-2011-02015 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) CDR0000665415 S0905 S0905 ( Other Identifier: SWOG ) S0905 ( Other Identifier: CTEP ) U10CA180830 ( U.S. NIH Grant/Contract ) U10CA180888 ( U.S. NIH Grant/Contract ) U10CA032102 ( U.S. NIH Grant/Contract ) |
| First Posted: | February 8, 2010 Key Record Dates |
| Results First Posted: | February 5, 2020 |
| Last Update Posted: | September 21, 2022 |
| Last Verified: | September 2022 |
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Mesothelioma Mesothelioma, Malignant Lung Neoplasms Adenoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Neoplasms, Mesothelial Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Pleural Neoplasms |
Lung Diseases Respiratory Tract Diseases Cisplatin Pemetrexed Cediranib Maleic acid Antineoplastic Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Folic Acid Antagonists Nucleic Acid Synthesis Inhibitors Protein Kinase Inhibitors |