Sirolimus and Pemetrexed to Treat Non-Small Cell Lung Cancer

NCT00923273 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 08007808-C-0078
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The drug pemetrexed is used to treat non-small cell lung cancer (NSCLC) that does not respond to standard therapy or that has recurred after standard therapy; however, only 9 in 100 patients respond to pemetrexed. Sirolimus is a drug that blocks a protein in cells called mammalian target of rapamycin (mTOR). In cancer cells, mTOR is active when it should not be, allowing the cells to grow uncontrollably. This protein is unusually active in many cases of NSCLC. By blocking the activity of mTOR, sirolimus may make the cancer cells more responsive to treatment with pemetrexed. Objectives: To determine if sirolimus in combination with pemetrexed is safe and well tolerated in patients with NSCLC. To determine the highest safe dose of pemetrexed combined with sirolimus. To look at the ability of sirolimus and pemetrexed to fight NSCLC. To learn how the body eliminates sirolimus and pemetrexed. Eligibility: Patients 18 years of age and older with NSCLC whose disease does not respond to standard therapy or has recurred after treatment with standard therapy. Design: Biopsy before treatment starts, if the tumor is easy to reach by bronchoscopy or can be done by needle biopsy. This procedure is optional. Drug treatment, as follows:

• Day 1: Intravenous (through a vein) infusions of pemetrexed. Small groups (3 to 6) of patients are given pemetrexed at a certain dose level. If the first group experiences no significant side effects, the next group receives a higher dose. This continues in succeeding groups for up to five dose levels until the maximum tolerated study dose (highest dose that patients can be given safely) is determined.
• To lessen the side effects of pemetrexed, patients also receive a Vitamin B12 injection every 21 days, folic acid tablets daily, and dexamethasone tablets twice a day the day before, the day of, and the day after pemetrexed infusions.
• Days 1-21: Sirolimus tablets by mouth. Evaluations during the treatment period:
• History and physical examinations, blood and urine tests, electrocardiogram.
• Disease evaluation with computed tomography (CT), positron emission tomography (PET) or magnetic resonance scans (MRI) scans....

Conditions

Carcinoma, Non-Small-Cell Lung

Keywords

Pemetrexed; Sirolimus; Non-Small Cell Lung Cancer; Phase I/II; mTOR Inhibitor; NSCLC; Lung Cancer

Outcome Measures

Primary Outcomes (3)

• Phase I: Maximum Tolerated Dose (MTD) of Pemetrexed

  The phase I component of the study are to determine the safety and tolerability of pemetrexed in human subjects with non small cell lung cancer (NSCLC), and to determine the maximum tolerated dose.

  5 weeks

• Phase II: Clinical Response Rate

  Clinical response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

  21 weeks

• Phase I: Maximum Tolerated Dose (MTD) of Sirolimus

  The phase I component of the study are to determine the safety and tolerability of sirolimus in human subjects with non small cell lung cancer (NSCLC), and to determine the maximum tolerated dose.

  5 weeks

Secondary Outcomes (1)

• Number of Participants With Serious and Non-Serious Adverse Events

  Date treatment consent signed to date off study, approximately 45 months

Study Arms (5)

Treatment level 1 - 3mg load

EXPERIMENTAL

Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m\^2

Drug: FDG-PET; Drug: Pemetrexed; Drug: Sirolimus; Dietary Supplement: Vitamin B12; Dietary Supplement: Folic acid tablets; Drug: Dexamethasone tablets

Treatment level 2 - 6 mg load

EXPERIMENTAL

Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2

Drug: FDG-PET; Drug: Pemetrexed; Drug: Sirolimus; Dietary Supplement: Vitamin B12; Dietary Supplement: Folic acid tablets; Drug: Dexamethasone tablets

Treatment level 3 - 6mg load

EXPERIMENTAL

Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2

Drug: FDG-PET; Drug: Pemetrexed; Drug: Sirolimus; Dietary Supplement: Vitamin B12; Dietary Supplement: Folic acid tablets; Drug: Dexamethasone tablets

Treatment level 4 - 10 mg load

EXPERIMENTAL

Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m\^2

Drug: FDG-PET; Drug: Pemetrexed; Drug: Sirolimus; Dietary Supplement: Vitamin B12; Dietary Supplement: Folic acid tablets; Drug: Dexamethasone tablets

Treatment level 5 - 15 mg load

EXPERIMENTAL

Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m\^2

Drug: FDG-PET; Drug: Pemetrexed; Drug: Sirolimus; Dietary Supplement: Vitamin B12; Dietary Supplement: Folic acid tablets; Drug: Dexamethasone tablets

Interventions

FDG-PET DRUG

PET CT will be performed at baseline and after two cycles of treatment.

Also known as: fluorodeoxyglucose positron emission tomography

Treatment level 1 - 3mg load; Treatment level 2 - 6 mg load; Treatment level 3 - 6mg load; Treatment level 4 - 10 mg load; Treatment level 5 - 15 mg load

Pemetrexed DRUG

Treatment level 1 - 3mg load; Treatment level 2 - 6 mg load; Treatment level 3 - 6mg load; Treatment level 4 - 10 mg load; Treatment level 5 - 15 mg load

Sirolimus DRUG

Treatment level 1 - 3mg load; Treatment level 2 - 6 mg load; Treatment level 3 - 6mg load; Treatment level 4 - 10 mg load; Treatment level 5 - 15 mg load

Vitamin B12 DIETARY_SUPPLEMENT

1000 micrograms intramuscularly every 63 days administered the preceding first dose of pemetrexed

Also known as: Cobalamin

Treatment level 1 - 3mg load; Treatment level 2 - 6 mg load; Treatment level 3 - 6mg load; Treatment level 4 - 10 mg load; Treatment level 5 - 15 mg load

Folic acid tablets DIETARY_SUPPLEMENT

1 mg dose every 63 days administered during the week preceding first dose of pemetrexed and will be continued for 21 days following last dose of pemetrexed.

Also known as: Folate

Treatment level 1 - 3mg load; Treatment level 2 - 6 mg load; Treatment level 3 - 6mg load; Treatment level 4 - 10 mg load; Treatment level 5 - 15 mg load

Dexamethasone tablets DRUG

4 mg dose twice daily the day before, the day of, and the day after pemetrexed.

Also known as: Decadron

Treatment level 1 - 3mg load; Treatment level 2 - 6 mg load; Treatment level 3 - 6mg load; Treatment level 4 - 10 mg load; Treatment level 5 - 15 mg load

Eligibility Criteria

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

You may qualify if:

• Histologically documented non small cell lung cancer (NSCLC) that is confirmed by the Laboratory of Pathology at the Clinical Center/National Institutes of Health (NIH) or the Laboratory of Pathology at National Naval Medical Center (NNMC).
• Tumor biopsy will be requested from all study subjects unless the procedure poses too great a risk. If the subject declines, he or she may still participate in the study. We will ask subjects not undergoing biopsy to provide 6 unstained slides or a tissue block of archived tissue for immunohistochemistry (IHC) evaluation. Tumors from subjects enrolling in the phase II portion of the study will be analyzed retrospectively to demonstrate mammalian target of rapamycin (mTOR) activation as assessed by immunohistochemistry in a fresh biopsy. mTOR activation will be defined using distribution and intensity of staining for phosphorylation of mTOR, or its downstream substrates S6 kinase (S6K), and S6. Standard operating procedures (SOPs) describing the acquisition and handling of PBMCs and tissues are outlined in appendix 10.3 and 10.4. At a minimum, a total score (sum of intensity and distribution scores) of 2 for phospho-S6 or phospho-mTOR (S2448) mTOR will be required to determine that mTOR is active. Either measurement will be sufficient to ascertain that mTOR is active. Measurement of phosphorylation of Akt, factor 4E binding protein 1 (4E-BP1), and total levels of thymidylate synthase (TS) will also be measured, but are not part of the eligibility requirements. In the event of limited tissue availability, the stains will be prioritized as follows: S6, mTOR, S6K, Akt (S473), Akt (T308), and TS. Phosphorylation of S6 correlates most closely with mTOR activity, while phosphorylation of mTOR at S2448 best predicts response to sirolimus.
• Tissue from the time of original diagnosis will be adequate for enrollment on study. Optional fresh tissue biopsy must be obtained AFTER their most recent chemotherapy (including small molecule or targeted therapy) or radiation therapy. Tumors that can be biopsied percutaneously (with or without computed tomography (CT)/ultrasound guidance) or via bronchoscopy will be considered accessible if there are no other competing risk factors such as coagulopathy, hypoxemia, unstable cardiovascular disease, uncontrolled pain, or inability to give informed consent.
• Individuals with relapsed NSCLC who have received at least one standard chemotherapeutic regimen are eligible. Patients who received adjuvant chemotherapy and then relapse or recur less than or equal to 12 months after completion of chemotherapy will be eligible. Patients who received adjuvant chemotherapy and relapse greater than 12 months after completion of chemotherapy should receive frontline therapy for metastatic disease before enrollment, as should individuals who initially present with incurable disease that is chemotherapy naive. Individuals unwilling to receive standard front line therapy for metastatic lung cancer may enroll.
• Patients must have not received any chemotherapy, biological, or radiation therapy in the 21 days prior to protocol enrollment. All previous chemo and radiation therapy induced toxicities must have resolved to grade 1 or less prior to enrollment.
• Because sirolimus may affect the efficacy of hormonal birth control via cytochrome P450 3A4 (CYP 3A4), study subjects of child bearing potential must be willing to use barrier birth control while receiving sirolimus therapy and for 12 weeks after discontinuation of sirolimus.
• Patients must have measurable disease for the phase II portion of the study.
• Age greater than or equal to 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
• An expected survival of at least 3 months.
• Patients must have the capacity to provide informed consent and demonstrate willingness to comply with an oral regimen.
• Patients must have normal organ and marrow function as defined below:
• Absolute neutrophil count greater than or equal to 1,500/mL.
• Platelets greater than or equal 100,000/mL.
• Total bilirubin less than 1.5 times upper limit of institutional normal.

You may not qualify if:

• Human immunodeficiency virus (HIV) positive patients.
• Pregnant or lactating women.
• Patients who received pemetrexed previously for Phase 1 only. Patients with prior pemetrexed are eligible for Phase 2.
• Patients who have had prior therapy with mTOR inhibitors such as sirolimus or its analogues within six months.
• Any concurrent therapy with chemotherapeutic agents or biologic agents or radiation therapy.
• Subjects with brain metastases may participate if the metastases are asymptomatic. Subjects are ineligible if brain metastases are symptomatic.
• Patients who are on the following drugs that modulate CYP3A4 and cannot replace these medications with other equivalent medications for the period of the study: amprenavir, atazanavir, bromocriptine, cimetidine, clarithromycin, clotrimazole, cyclosporine, danazol, diltiazem, erythromycin, fluconazole, fosamprenavir, other HIV protease inhibitors, indinavir, itraconazole, ketoconazole, metoclopramide, nefazodone, nelfinavir, nicardipine, nifedipine, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), verapamil, voriconazole, nevirapine, rifampicin, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St. John's Wort.
• Subjects taking non steroidal anti-inflammatory agents who are unable to stop or replace the agents for the 5 days prior to and the 2 days after pemetrexed will not be eligible.
• Patients who have received live vaccines in the past 21 days.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics, 2005. CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30. doi: 10.3322/canjclin.55.1.10.

  PMID: 15661684 BACKGROUND

• Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. doi: 10.1056/NEJMoa011954.

  PMID: 11784875 BACKGROUND

• Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000 Jun;18(12):2354-62. doi: 10.1200/JCO.2000.18.12.2354.

  PMID: 10856094 BACKGROUND

• Komiya T, Memmott RM, Blumenthal GM, Bernstein W, Ballas MS, De Chowdhury R, Chun G, Peer CJ, Figg WD, Liewehr DJ, Steinberg SM, Giaccone G, Szabo E, Kawabata S, Tsurutani J, Rajan A, Dennis PA. A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer. Transl Lung Cancer Res. 2019 Jun;8(3):247-257. doi: 10.21037/tlcr.2019.04.19.

  PMID: 31367538 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Lung Neoplasms

Interventions

Pemetrexed; Sirolimus; Vitamin B 12; Folic Acid; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial 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; Macrolides; Lactones; Organic Chemicals; Corrinoids; Tetrapyrroles; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds, 4 or More Rings; Macrocyclic Compounds; Polycyclic Compounds; Pterins; Pteridines; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Dr. Arun Rajan
• Organization: National Cancer Institute

rajana@mail.nih.gov

301-594-5322

Study Officials

• Arun Rajan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: February 29, 2008
• Primary Completion: March 10, 2013
• Study Completion: March 10, 2013
• Last Updated: November 26, 2019
• Results First Posted: October 23, 2013

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)