Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Temsirolimus and pemetrexed for recurrent or refractory NSCLC
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.
Interventions
DRUGPemetrexed
DRUGTemsirolimus
Sponsors
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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: 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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. |
Countries
United States
Participant flow
Recruitment details
The study opened to participant enrollment on 09/28/2009 and closed to participant enrollment on 12/20/2011.
Participants by arm
| Arm | Count |
|---|---|
| Phase I (Premetrexed & Temsirolimus) * Participants enrolled in the Phase I portion Dose Level 1 received:
* Pemetrexed 500mg/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
* Participants enrolled in the Phase I portion Dose Level -1 received:
* Pemetrexed 375mg/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 | 8 |
| Phase 2 (Pemetrexed & Temsirolimus) -Participants enrolled in the Phase 2 portion received:
* Pemetrexed (375 mg/m2\^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 | 4 |
| Total | 12 |
Baseline characteristics
| Characteristic | Phase I (Premetrexed & Temsirolimus) | Phase 2 (Pemetrexed & Temsirolimus) | Total |
|---|---|---|---|
| Age, Continuous | 58.5 years | 67.5 years | 62.5 years |
| Region of Enrollment United States | 8 participants | 4 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 4 / 4 |
| serious Total, serious adverse events | 2 / 8 | 2 / 4 |
Outcome results
Primary
Phase I and Phase II: Overall Response Rate (Complete Response + Partial Response)
* 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
Time frame: 2 years
Population: (4) patients in Phase 1 were not evaluable for response as they were removed from study prior to week 6 scans. One patient in Phase 2 was not evaluable due to expiring prior to week 6 scans.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Premetrexed & Temsirolimus) | Phase I and Phase II: Overall Response Rate (Complete Response + Partial Response) | 0 percentage of participants |
| Phase 2 (Pemetrexed & Temsirolimus) | Phase I and Phase II: Overall Response Rate (Complete Response + Partial Response) | 33.3 percentage of participants |
Primary
Phase I Only: Maximum Tolerated Dose (MTD) of Pemetrexed That Could be Administered Weekly in Combination With Temsirolimus
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.
Time frame: Completion of first cycle by all enrolled patients in Phase I portion of study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Premetrexed & Temsirolimus) | Phase I Only: Maximum Tolerated Dose (MTD) of Pemetrexed That Could be Administered Weekly in Combination With Temsirolimus | 375 mg/m^2 |
Primary
Phase I Only: Maximum Tolerated Dose (MTD) of Temsirolimus That Could be Administered Weekly in Combination With Pemetrexed
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.
Time frame: Completion of first cycle by all enrolled patients in Phase I portion of study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Premetrexed & Temsirolimus) | Phase I Only: Maximum Tolerated Dose (MTD) of Temsirolimus That Could be Administered Weekly in Combination With Pemetrexed | 15 mg |
Primary
Phase I Only: Number of Participants Who Experience Dose-limiting Toxicities (DLT) of Temsirolimus and Pemetrexed
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.
Time frame: Completion of first cycle (approximately 21 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Premetrexed & Temsirolimus) | Phase I Only: Number of Participants Who Experience Dose-limiting Toxicities (DLT) of Temsirolimus and Pemetrexed | 2 participants |
| Phase 2 (Pemetrexed & Temsirolimus) | Phase I Only: Number of Participants Who Experience Dose-limiting Toxicities (DLT) of Temsirolimus and Pemetrexed | 0 participants |
Primary
Phase I Only: Phospho-Akt Levels in Circulating Mononuclear Cells
Time frame: Cycle 1 Day 1, one hour post completion of initial temsirolimus dose, and Cycle 1 Day 8
Population: Due to early termination of the study by withdrawal of funding by sponsor (Pfizer merged with Wyeth), the peripheral blood samples that were collected for this outcome measure were not analyzed prior to losing funding.
Primary
Phase I Only: Phospho-S6 Levels in Circulating Mononuclear Cells
Time frame: Cycle 1 Day 1, one hour post completion of initial temsirolimus dose, and Cycle 1 Day 8
Population: Due to early termination of the study by withdrawal of funding by sponsor (Pfizer merged with Wyeth), the peripheral blood samples that were collected for this outcome measure were not analyzed prior to losing funding.
Secondary
Phase 2 Only: Phospho-Akt Levels in Circulating Mononuclear Cells
Time frame: Cycle 1 Day 1, one hour post completion of initial temsirolimus dose, and Cycle 1 Day 8
Population: Due to early termination of the study by withdrawal of funding by sponsor (Pfizer merged with Wyeth), the peripheral blood samples that were collected for this outcome measure were not analyzed prior to losing funding.
Secondary
Phase 2 Only: Phospho-S6 Levels in Circulating Mononuclear Cells Before and After Treatment
Time frame: Cycle 1 Day 1, one hour post completion of initial temsirolimus dose, and Cycle 1 Day 8
Population: Due to early termination of the study by withdrawal of funding by sponsor (Pfizer merged with Wyeth), the peripheral blood samples that were collected for this outcome measure were not analyzed prior to losing funding.
Secondary
Phase 2 Only: Progression-free Survival (PFS)
PFS is defined as the duration of time from start of treatment to time of progression.
Time frame: 2 years from completion of treatment
Population: There were only (2) patients evaluable for PFS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 2 (Pemetrexed & Temsirolimus) | Phase 2 Only: Progression-free Survival (PFS) | Patient A | 523 days |
| Phase 2 (Pemetrexed & Temsirolimus) | Phase 2 Only: Progression-free Survival (PFS) | Patient B | 167 days |
Secondary
Phase 2 Only: Survival Rate
Time frame: 1 year after start of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2 (Pemetrexed & Temsirolimus) | Phase 2 Only: Survival Rate | 50 percentage of participants |