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

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

A Phase I/II Trial of Temsirolimus and Pemetrexed in Recurrent/Refractory Non Small Cell Lung Cancer (NSCLC)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00921310
• Other study ID #: 09-0668 / 201105207
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: June 15, 2009
• Last updated: July 21, 2014
• Start date: September 2009
• Est. completion date: May 2015

Study information

• Verified date: July 2014
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 12
• Est. completion date: May 2015
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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., 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

• AST(SGOT)/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

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung

Intervention

Drug:
• Pemetrexed

• Temsirolimus

Locations

Country	Name	City	State
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (6)

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. — View Citation

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. Epub 2006 Oct 10. — View Citation

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. Review. — View Citation

Peralba JM, DeGraffenried L, Friedrichs W, Fulcher L, Grünwald 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. — View Citation

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. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase I - determine the maximum tolerated dose (MTD) of temsirolimus that could be administered weekly in combination with pemetrexed.		Completion of first cycle by all enrolled patients	Yes
Primary	Phase I - determine the dose-limiting toxicity (DLT) of temsirolimus and pemetrexed as well as other toxicities of this combination therapy.		Completion of first cycle (approximately 21 days)	Yes
Primary	Phase I - describe the response rate of the combination in patients with non-small cell lung cancer (NSCLC).		2 years	No
Primary	Phase I - describe phospho-Akt and 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	No
Primary	Phase 2 - determine the response rates in patients with NSCLC when treated with temsirolimus and pemetrexed.		2 years	No
Secondary	Phase 2 - evaluate progression-free survival in patients with NSCLC when treated with temsirolimus and pemetrexed.		2 years	No
Secondary	Phase 2 - determine the one-year survival rates in patients with NSCLC when treated with temsirolimus and pemetrexed.		1 year	No
Secondary	Phase 2 - describe phospho-Akt and 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	No

External Links

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