Temsirolimus and Pemetrexed for Recurrent or Refractory Non-Small Cell Lung Cancer

Phase 1

Terminated

Conditions: Carcinoma, Non-Small-Cell Lung

Interventions: Drug: Pemetrexed
Drug: Temsirolimus

Registration Number: NCT00921310

Lead Sponsor: Washington University School of Medicine

Brief Summary: To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the combination of temsirolimus and pemetrexed, as well as the response rate. The starting dose (Dose Level 1) and schedule of pemetrexed will be 500 mg/m\^2 given every 3 weeks and the starting dose (Dose Level 1) for temsirolimus will be 15 mg given weekly for 3 weeks, to complete 1 cycle. In subsequent cohorts, dose will be escalated or de-escalated. Enrollment to each cohort is based on toxicity experienced at that dose level.

Detailed Description: * To determine the maximum tolerated dose (MTD) of temsirolimus that could be administered weekly in combination with pemetrexed.

* To determine the dose-limiting toxicity (DLT) of temsirolimus and pemetrexed as well as other toxicities of this combination therapy.

* To describe the response rate of the combination in patients with relapsed/refractory non-small cell lung cancer (NSCLC).

* To describe phospho-Akt and phospho-S6 levels in circulating mononuclear cells before and after treatment.

* To determine the response rates in patients with NSCLC when treated with temsirolimus and pemetrexed.

* To evaluate progression-free survival in patients with NSCLC when treated with temsirolimus and pemetrexed.

* To determine the one-year survival rates in patients with NSCLC when treated with temsirolimus and pemetrexed.

* To describe phospho-Akt and phospho-S6 levels in circulating mononuclear cells before and after treatment.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Patients must have histologically or cytologically confirmed diagnosis of NSCLC.
Patients must have non-squamous histology.
Patients must have measurable disease (by RECIST criteria), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan.
Patients may have failed at least one prior platinum-based therapy for NSCLC or be candidates for first-line therapy for advanced disease deemed ineligible to receive platinum-based chemotherapy in the opinion of the treating physician (e.g., Eastern Cooperative Oncology Group (ECOG) performance status of 2, age ≥ 70, chronic medical condition).
Patients must be at least 4 weeks out from chemotherapy, biological therapy, major surgery, or any investigative therapy and must have recovered from any toxicities. Patients must be at least 2 weeks out from prior radiation therapy and must have recovered from any associated toxicities (with the exception of alopecia).
Patients must be at least 3 weeks out from immunosuppressive therapy (except corticosteroids used as antiemetics).
Age ≥18 years. Because no dosing or adverse event data are currently available on the use of pemetrexed in combination with temsirolimus in patients <18 years of age, children are excluded from this study.
ECOG performance status 0-2.
Patients must have normal organ and marrow function as defined below:
- hemoglobin ≥9.0 g/dL
- absolute neutrophil count ≥1,500/mcL
- platelets ≥100,000/mcL
- total bilirubin ≤1.5 mg/dL
- aspartate aminotransferase (AST)(SGOT)/ alanine aminotransferase (ALT) (SGPT) ≤2.5 X institutional upper limit of normal OR ≤5 X institutional upper limit of normal if enzyme abnormalities are due to liver metastases
- creatinine < 2.0 mg/dL AND/OR
- creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
- serum cholesterol < 350 mg/dL
- triglycerides < 300 mg/dL
The effects of pemetrexed and temsirolimus on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because antifolate antineoplastic agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Ability of the patient (or legally authorized representative if applicable) to understand and the willingness to sign a written informed consent document.
Both men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria

Patients who have had previous treatment with pemetrexed.
Patients may not be receiving any other investigational agents.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, clinically significant hepatic or renal disease or neuropathy greater than grade 2.
Symptomatic brain metastases
Presence of a third-space fluid (pleural effusion, ascites etc.) that is uncontrolled by drainage.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to temsirolimus, its metabolites (including sirolimus), its components, and/or polysorbate 80, or to other agents used in the study.
Known hypersensitivity to macrolide antibiotics.
Patients with psychiatric illness/social situations that would limit compliance with study requirements and with premedications of dexamethasone, folic acid and vitamin B12.
Patients with inability to discontinue all non-steroidal anti-inflammatory drugs (NSAIDS).
Patients taking anticonvulsant medications (Carbamezapine, phenytoin, fosphenytoin, phenobarbital).
Patients taking anti-arrhythmic medications (amiodarone, diltiazem and quinidine).
Patients may not be taking medications known as inhibitors of CYP3A4 (carbamezapine, phenytoin, phenobarbital, rifampin, St. John's wort). Use of inducers of CYP3A4 is discouraged but not specifically prohibited. Dexamethasone as a chronic medication is discouraged.
Pregnant women are excluded from this study because pemetrexed is an antifolate antineoplastic drug with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pemetrexed, breastfeeding should be discontinued if the mother is treated with pemetrexed. These potential risks may also apply to other agents used in this study.
Patients with known concomitant genetic or acquired immunosuppressive diseases are excluded. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pemetrexed and temsirolimus. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I Dose Level 1 (pemetrexed + temsirolimus)	Temsirolimus	-Dose Level 1 * Pemetrexed 500mg/m\^2 intravenous (IV) on Day 1 of each 21 day cycle * Temsirolimus 15 mg IV on Days 1,8 and 15 of each 21 day cycle
Phase I Dose Level -1 (pemetrexed + temsirolimus)	Temsirolimus	* Pemetrexed (375 mg/m\^2) IV on Day 1 of each 21 day cycle * Temsirolimus (15 mg) IV on Days 1,8 and 15 of each 21 day cycle
Phase I Dose Level 1 (pemetrexed + temsirolimus)	Pemetrexed	-Dose Level 1 * Pemetrexed 500mg/m\^2 intravenous (IV) on Day 1 of each 21 day cycle * Temsirolimus 15 mg IV on Days 1,8 and 15 of each 21 day cycle
Phase I Dose Level -1 (pemetrexed + temsirolimus)	Pemetrexed	* Pemetrexed (375 mg/m\^2) IV on Day 1 of each 21 day cycle * Temsirolimus (15 mg) IV on Days 1,8 and 15 of each 21 day cycle
Phase 2 (pemetrexed + temsirolimus)	Pemetrexed	* Phase 2 dose will be the maximum tolerated dose found in the Phase I portion of the study. * Pemetrexed (375 mg/m\^2) IV on Day 1 of each 21 day cycle * Temsirolimus (15 mg) IV on Days 1,8 and 15 of each 21 day cycle
Phase 2 (pemetrexed + temsirolimus)	Temsirolimus	* Phase 2 dose will be the maximum tolerated dose found in the Phase I portion of the study. * Pemetrexed (375 mg/m\^2) IV on Day 1 of each 21 day cycle * Temsirolimus (15 mg) IV on Days 1,8 and 15 of each 21 day cycle

Primary Outcome Measures

Name	Time	Method
Phase I Only: Maximum Tolerated Dose (MTD) of Pemetrexed That Could be Administered Weekly in Combination With Temsirolimus	Completion of first cycle by all enrolled patients in Phase I portion of study	The starting dose and schedule of pemetrexed will be 500 mg/m2 given every 3 weeks and the starting dose for temsirolimus will be 15 mg given weekly for 3 weeks, to complete 1 cycle. In subsequent cohorts, dose will be escalated or de-escalated. Enrollment to each cohort is based on toxicity experienced at that dose level. The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort experience dose-limiting toxicity during the first cycle. Six patients will be enrolled at the maximum tolerated dose to ensure that no more than 2 DLTs occur at the MTD. Dose escalations will proceed until the MTD has been reached.
Phase I Only: Maximum Tolerated Dose (MTD) of Temsirolimus That Could be Administered Weekly in Combination With Pemetrexed	Completion of first cycle by all enrolled patients in Phase I portion of study	The starting dose and schedule of pemetrexed will be 500 mg/m2 given every 3 weeks and the starting dose for temsirolimus will be 15 mg given weekly for 3 weeks, to complete 1 cycle. In subsequent cohorts, dose will be escalated or de-escalated. Enrollment to each cohort is based on toxicity experienced at that dose level. The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort experience dose-limiting toxicity during the first cycle. Six patients will be enrolled at the maximum tolerated dose to ensure that no more than 2 DLTs occur at the MTD. Dose escalations will proceed until the MTD has been reached.
Phase I Only: Number of Participants Who Experience Dose-limiting Toxicities (DLT) of Temsirolimus and Pemetrexed	Completion of first cycle (approximately 21 days)	DLT will be defined as occurring within the first cycle of Phase I only and will be graded according to the Common Terminology Criteria for Adverse Events v 3.0 (CTCAE) * Any grade 3 or higher hematologic toxicity with the exception of anemia. * Any grade 3 or higher non-hematologic toxicity related to study therapy (except alopecia). * Grade 3 or 4 pneumonitis or esophagitis. * Treatment delay of temsirolimus for more than 14 consecutive days due to study-related toxicity. * Treatment delay of pemetrexed therapy for more than 14 consecutive days because of study-related toxicity.
Phase I and Phase II: Overall Response Rate (Complete Response + Partial Response)	2 years	* Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. * Complete response (CR)-disappearance of all target lesions and disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR)-at least a 30% decrease in the sum of the longest diameter (LD) of the target lesions taking as reference the baseline sum LD
Phase I Only: Phospho-Akt Levels in Circulating Mononuclear Cells	Cycle 1 Day 1, one hour post completion of initial temsirolimus dose, and Cycle 1 Day 8
Phase I Only: Phospho-S6 Levels in Circulating Mononuclear Cells	Cycle 1 Day 1, one hour post completion of initial temsirolimus dose, and Cycle 1 Day 8

Secondary Outcome Measures

Name	Time	Method
Phase 2 Only: Progression-free Survival (PFS)	2 years from completion of treatment	PFS is defined as the duration of time from start of treatment to time of progression.
Phase 2 Only: Survival Rate	1 year after start of treatment
Phase 2 Only: Phospho-Akt Levels in Circulating Mononuclear Cells	Cycle 1 Day 1, one hour post completion of initial temsirolimus dose, and Cycle 1 Day 8
Phase 2 Only: Phospho-S6 Levels in Circulating Mononuclear Cells Before and After Treatment	Cycle 1 Day 1, one hour post completion of initial temsirolimus dose, and Cycle 1 Day 8