S1300: Pemetrexed Disodium With or Without Crizotinib in Treating Patients With Stage IV Non-Small Cell Lung Cancer That Has Progressed After Crizotinib

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial studies how well pemetrexed disodium with or without crizotinib works in treating patients with stage IV non-small cell lung cancer that has progressed after crizotinib. Drugs used in chemotherapy, such as pemetrexed disodium, 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. Crizotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving pemetrexed disodium is more effective with or without crizotinib in treating patients with non-small cell lung cancer that has progressed after crizotinib.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To evaluate the efficacy of the combination of crizotinib and pemetrexed (pemetrexed disodium) compared to pemetrexed monotherapy as measured by progression-free survival (PFS) in anaplastic lymphoma kinase (ALK)+ non-squamous non-small cell lung cancer (NSCLC) patients who achieved clinical benefit with crizotinib monotherapy and subsequently progressed systemically. SECONDARY OBJECTIVES: I. To compare the response rate (confirmed and unconfirmed, complete and partial responses) in patients randomized to receive pemetrexed monotherapy to historical data. II. To assess overall survival in both arms. III. To evaluate the patterns of failure (central nervous system [CNS], extra-CNS) of the combination of crizotinib and pemetrexed and of pemetrexed monotherapy in ALK+ non-squamous NSCLC after progression on crizotinib. IV. To evaluate the frequency and severity of toxicities resulting from the administration of crizotinib and pemetrexed compared to pemetrexed monotherapy. V. To evaluate PFS and the response rate in patients treated with crizotinib following progression on the pemetrexed monotherapy arm. TERTIARY OBJECTIVES: I. To compare progression-free survival (PFS) and response rates (RR) between ALK dominant and ALK non-dominant patients in the entire study population and within each treatment arm. II. To evaluate if the magnitude of difference in these outcomes between ALK dominant and ALK non-dominant patients varies by treatment arm. III. To assess blood biomarkers of sensitivity and resistance to crizotinib and pemetrexed in an exploratory manner. The blood biomarkers include cell free circulating deoxyribonucleic acid (DNA), micro ribonucleic acid (microRNA) before treatment, during treatment (after 2 cycles) and at treatment progression. IV. To assess pharmacogenomic factors in peripheral blood that might affect the drug level and treatment outcomes in an exploratory manner. V. To assess proteomic/immunologic parameters that might affect the treatment outcomes in an exploratory manner. VI. To evaluate the frequency of individual mechanisms of resistance (copy number gain [CNG], mutation, alternate oncogene). VII. To identify alternative driver mechanisms in ALK fluorescence in situ hybridization positive (FISH+) otherwise unknown. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive crizotinib orally (PO) twice daily (BID) on days 1-21 and pemetrexed disodium intravenously (IV) over 10 minutes on day 1. ARM II: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Upon disease progression or symptomatic deterioration, patients may crossover to Arm I. In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 3 years.

Official Title
-----------------
S1300: A Randomized, Phase II Trial of Crizotinib Plus Pemetrexed Versus Pemetrexed Monotherapy in ALK-Positive Non-squamous NSCLC Patients Who Have Progressed Systemically After Previous Clinical Benefit From Crizotinib Monotherapy

Conditions
-----------------
Adenocarcinoma of the Lung, Large Cell Lung Cancer, Recurrent Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: crizotinib
* Drug: pemetrexed disodium
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically or cytologically proven primary non-squamous non-small cell lung cancer (adenocarcinoma, large cell carcinoma, adenocarcinoma in situ, mixed histology with < 50% squamous or unspecified); patients with tumors having squamous cell components >= 50% are not eligible; disease must be stage IV Patients must have documented ALK positivity at the time of initial crizotinib monotherapy using the Vysis Break-Apart FISH assay (or other Food and Drug Administration [FDA]-approved diagnostic test); samples are deemed to be FISH-positive if greater than or equal to 15% of scored tumor cells had split ALK 5' and 3' probe signals or had isolated 3' signal; FISH status must be documented on the Onstudy Form and a copy of the pathology report from the Vysis Break-Apart FISH assay (or other FDA-approved diagnostic test) must be submitted Prior to registration, patients must have achieved clinical benefit with crizotinib monotherapy and subsequently have systemically progressed; clinical benefit is defined as having stable disease on crizotinib monotherapy for at least 90 days or achieving a confirmed partial or complete response; systemic progression is defined as progressive disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, excluding progression based on brain/CNS metastases alone Patients must have received crizotinib monotherapy at 250 mg BID on a continuous dosing schedule for at least 90 days; patients must be planning to start treatment at least three days, but no more than 30 days after discontinuing crizotinib monotherapy; patients who were not able to tolerate 250 mg BID of crizotinib are not eligible for this study Patients must be pemetrexed-naïve; patients may have received any number of prior chemotherapy or molecularly targeted agents; if crizotinib was used in the 1st line setting then chemotherapy naive patients are also eligible; if patient received crizotinib in combination with chemotherapy, prior chemotherapy must have been discontinued at least 14 days prior to registration and all adverse events must have resolved to =< grade 1 Patients must have measurable disease per RECIST documented by computed tomography (CT) or magnetic resonance imaging (MRI); the CT from a combined positron emission tomography (PET)/CT may be used to document only non-measurable disease unless it is of diagnostic quality; measurable disease must be assessed within 28 days prior to registration; pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease; non-measurable disease must be assessed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form RECIST 1.1 Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to registration; patient must not have brain metastases unless: (1) metastases have been treated and have remained controlled for at least 14 days following treatment or was not treated, but is asymptomatic, AND (2) patient has no residual neurological dysfunction off corticosteroids or anti-convulsants for at least 14 days Patients may have received palliative radiotherapy to non-target lesions within 14 days prior to registration provided all radiotherapy related toxicities have resolved to =< grade 1 prior to registration; patients must not have received any major surgery within 28 days prior to registration Patients must not have had any prior exposure to heat shock protein (HSP)90 inhibitors (such as IPI-504 or ganetespib) or non-crizotinib ALK inhibitors (such as AP26113 or LDK378) Patients must be offered participation in the translational medicine studies; additionally if patient has biopsy accessible disease they must be offered participation in the translational medicine studies Absolute neutrophil count (ANC) >= 1,500/ul Platelet count >= 100,000/ul Hemoglobin >= 9 g/dL Serum bilirubin =< 2 X institutional upper limit of normal (IULN) Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x IULN Estimated (calculated) or measured glomerular filtration rate >= 45 mL/min (or 45 mL/min/1.73 m^2); creatinine (mg/dl) used in calculation (Cockroft-Gault) must be obtained within 28 days prior to registration Male patients must have free and total testosterone level obtained within 28 days prior to registration Pre-study history and physical must be obtained with 28 days prior to registration Patients must have Zubrod performance status 0-2 within 28 days prior to registration Patients must be able to swallow capsules Patients must have corrected QT (QTC) interval =< 480 msec on electrocardiogram (EKG) at baseline; patient with congenital long QT syndrome are not eligible 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 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 REGULATORY CRITERIA: Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines REGULATORY CRITERIA: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system CROSSOVER (STEP 2) REGISTRATION: Patients must have progressed systemically on Arm 2 of this study (pemetrexed monotherapy) CROSSOVER (STEP 2) REGISTRATION: Patients must be registered to crossover (Step 2) within 30 days of discontinuing treatment on Arm 2 of this study CROSSOVER (STEP 2) REGISTRATION: ANC >= 1,500/ul CROSSOVER (STEP 2) REGISTRATION: Platelet count >= 100,000/ul CROSSOVER (STEP 2) REGISTRATION: Serum bilirubin =< 2 X IULN CROSSOVER (STEP 2) REGISTRATION: SGOT (AST) or SGPT (ALT) =< 2.5 x IULN CROSSOVER (STEP 2) REGISTRATION: estimated (calculated) or measured glomerular filtration rate >= 45 mL/min (or 45 mL/min/1.73 m^2) within 28 days prior to registration; creatinine (mg/dl) used in calculation (Cockroft-Gault) must be obtained within 28 days prior to registration CROSSOVER (STEP 2) REGISTRATION: male patients must have free and total testosterone level obtained within 28 days prior to Crossover (Step 2) Registration CROSSOVER (STEP 2) REGISTRATION: patients must have Zubrod performance status 0-2 within 28 days prior to Crossover (Step 2) Registration

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (crizotinib, pemetrexed disodium)<br>Patients receive crizotinib PO BID on days 1-21 and pemetrexed disodium IV over 10 minutes on day 1. | Drug: crizotinib<br>* Given PO<br>* Other names: PF-02341066;Drug: pemetrexed disodium<br>* Given IV<br>* Other names: MTA;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Arm II (pemetrexed disodium)<br>ARM II: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Upon disease progression or symptomatic deterioration, patients may crossover to Arm I. | Drug: pemetrexed disodium<br>* Given IV<br>* Other names: MTA;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS Between Patients Randomized to Receive Pemetrexed Disodium Monotherapy Versus Crizotinib and Pemetrexed Disodium Combination Therapy | A stratified log-rank test at the 0.10 level will be used to test the primary hypothesis comparing the two treatment arms. | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events of Crizotinib in Combination With Pemetrexed Disodium, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Comparisons of toxicities rates will be done using a Fisher's exact or chi-squared test of independence, when appropriate using 10% as the significance threshold. Within each treatment arm, any toxicity with at least 5% prevalence has at least a 95% chance of being observed. | Up to 3 years | 
| Response Rate (Confirmed and Unconfirmed) With Pemetrexed Disodium Monotherapy | Comparisons of response rates will be done using a chi-square test of independence using 10% as the significance threshold. Within each treatment arm, response rates can be estimated to within 13% (with 95% confidence). | Up to 3 years | 
| Response Rates (Confirmed and Unconfirmed) of Crizotinib With Pemetrexed Disodium | Comparisons of response rates will be done using a chi-square test of independence using 10% as the significance threshold. Within each treatment arm, response rates can be estimated to within 13% (with 95% confidence). | Up to 3 years | 
| Patterns of Failure | Defined as CNS-only, extra-CNS, and both CNS and extra-CNS progression between the treatment arms. Evaluated within each treatment arm using cumulative incidence curves. | Up to 3 years | 
| Overall Survival | Differences in OS by treatment arm will be evaluated using a 1-sided log-rank test with significant level of 10%. | Up to 3 years |