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

NCT00921310 | Terminated Phase 1 Results

• 1 other identifier: 09-0668 / 201105207
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Carcinoma, Non-Small-Cell Lung

Keywords

Temsirolimus and pemetrexed for recurrent or refractory NSCLC

Outcome Measures

Primary Outcomes (6)

• 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.

  Completion of first cycle by all enrolled patients in Phase I portion of study

• 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.

  Completion of first cycle by all enrolled patients in Phase I portion of study

• 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.

  Completion of first cycle (approximately 21 days)

• 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

  2 years

• 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 Outcomes (4)

• Phase 2 Only: Progression-free Survival (PFS)

  2 years from completion of treatment

• 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

Study Arms (3)

Phase I Dose Level 1 (pemetrexed + temsirolimus)

EXPERIMENTAL

-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

Drug: Pemetrexed; Drug: Temsirolimus

Phase I Dose Level -1 (pemetrexed + temsirolimus)

EXPERIMENTAL

* 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

Drug: Pemetrexed; Drug: Temsirolimus

Phase 2 (pemetrexed + temsirolimus)

EXPERIMENTAL

* 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

Drug: Pemetrexed; Drug: Temsirolimus

Interventions

Pemetrexed DRUG

Also known as: Alimta

Phase 2 (pemetrexed + temsirolimus); Phase I Dose Level -1 (pemetrexed + temsirolimus); Phase I Dose Level 1 (pemetrexed + temsirolimus)

Temsirolimus DRUG

Also known as: Torisel

Phase 2 (pemetrexed + temsirolimus); Phase I Dose Level -1 (pemetrexed + temsirolimus); Phase I Dose Level 1 (pemetrexed + temsirolimus)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (6)

• Russo F, Bearz A, Pampaloni G; Investigators of Italian Pemetrexed Monotherapy of NSCLC Group. Pemetrexed single agent chemotherapy in previously treated patients with locally advanced or metastatic non-small cell lung cancer. BMC Cancer. 2008 Jul 31;8:216. doi: 10.1186/1471-2407-8-216.

  PMID: 18667090 BACKGROUND

• Pal SK, Figlin RA, Reckamp KL. The role of targeting mammalian target of rapamycin in lung cancer. Clin Lung Cancer. 2008 Nov;9(6):340-5. doi: 10.3816/CLC.2008.n.049.

  PMID: 19073516 BACKGROUND

• Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004 Mar 1;22(5):909-18. doi: 10.1200/JCO.2004.08.185.

  PMID: 14990647 BACKGROUND

• Rini BI. Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin Cancer Res. 2008 Mar 1;14(5):1286-90. doi: 10.1158/1078-0432.CCR-07-4719. No abstract available.

  PMID: 18316545 BACKGROUND

• Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, Le L, Oza A, Nicklee T, Ho J, Birle D, Pond GR, Arboine D, Dancey J, Aviel-Ronen S, Tsao MS, Hedley D, Siu LL. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. 2006 Nov 6;95(9):1148-54. doi: 10.1038/sj.bjc.6603419. Epub 2006 Oct 10.

  PMID: 17031397 BACKGROUND

• Peralba JM, DeGraffenried L, Friedrichs W, Fulcher L, Grunwald V, Weiss G, Hidalgo M. Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients. Clin Cancer Res. 2003 Aug 1;9(8):2887-92.

  PMID: 12912932 BACKGROUND

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Pemetrexed; temsirolimus

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Results Point of Contact

• Title: Maria Baggstrom, M.D.
• Organization: Washington University School of Medicine

mbaggstr@dom.wustl.edu

314-362-5737

Study Officials

• Maria Baggstrom, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2009
• First Posted: June 16, 2009
• Study Start: September 1, 2009
• Primary Completion: January 1, 2013
• Study Completion: April 1, 2016
• Last Updated: December 13, 2016
• Results First Posted: December 13, 2016

Record last verified: 2016-10

Locations

US (1)