-02341066 and PF-00299804 for Advanced Non-Small Cell Lung Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01441128
First received: September 24, 2011
Last updated: August 23, 2014
Last verified: April 2014
  Purpose

Background:

- PF-02341066 and PF-00299804 are drugs that specifically target certain proteins that may be more active in cancer cells than normal cells, in particular in non-small cell lung cancer. Both drugs seem to be able to stop the growth of or kill cancer cells. Researchers want to combine them to see if they are a safe and effective treatment for advanced non-small cell lung cancer.

Objectives:

- To test the safety and effectiveness of PF-02341066 and PF-00299804 for advanced non-small cell lung cancer.

Eligibility:

- Individuals at least 18 years of age with advanced non-small cell lung cancer that has not responded to standard treatments.

Design:

  • Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, and imaging studies. Heart and lung function tests and an eye exam may also be given.
  • The first cycle of treatment will be 28 days. Every cycle after the first will be 21 days. Participants may have up to 17 cycles of treatment.
  • Participants will take both study drugs as tablets. Twelve hours after the first dose, participants will take only the PF-02341066. This dose schedule will remain the same throughout the study.
  • Participants will be monitored with frequent blood and urine tests and imaging studies. Tumor biopsies will be taken as needed. Those in the study will keep a diary to record any symptoms or side effects of taking the study drugs.
  • After 17 cycles of treatment, or after stopping the study drugs early for any other reason, participants will have a final followup visit.

Condition Intervention Phase
Carcinoma, Non-Small Cell Lung
Adenocarcinoma
Carcinoma, Squamous Cell
Carcinoma, Large Cell
Drug: PF-02341066/PF-00299804
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Dose Escalation Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Combined Oral C-Met/ALK Inhibitor (PF-02341066) and Pan-Her Inhibitor (PF-0299804) in Patients With Advanced Non-Small Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Overall safety profile of combined PF 02341066 plus PF 00299804 including adverse events (AE), as defined and graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], and first cycle Dose Limiting Tox... [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Plasma concentrations and pharmacokinetic (PK) parameters of PF 02341066 and PF 00299804 including AUCtau, Cmax, Ctrough, Tmax, and CLss/F [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Clinical activity of combined PF 02341066 plus PF 00299804 including objective response (OR) and stable disease (SD) as defined by RECIST version 1.1, duration of response (DR) and progression free survival (PFS). [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • Biomarkers in tumor and blood that are potentially predictive for drug activity: for example, KRAS mutations, EGFR mutations (eg, T790M), EGFR and HER2 amplifications, c Met amplification and mutations, ALK, PTEN and PIK3A status in tumor biopsi... [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacodynamic biomarkers in tumor biopsies (e.g., phospho c Met, c Met, EGFR, phospho EGFR) and in blood (e.g., HGF and s Met) that are modulated following drug exposure. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Enrollment: 20
Study Start Date: September 2011
Study Completion Date: May 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
The starting doses will be 200 mg by mouth, twice a day of PF 02341066 in tablet form and 30 mg by mouth once a day of PF 0029804 in tablet form. Thedose of each drug in the combination will be escalated or de-escalated until the maximum tolerated combined dose is reached. Patients will then be treated with the maximum tolerated combined dose.
Drug: PF-02341066/PF-00299804
Combined PF-02341066 and PF-00299804
Drug: PF-02341066/PF-00299804
Single Agent PF-00299804 followed by Combined PF-02341066 and PF-00299804
Experimental: Arm 2
45 mg by mouth once a day of PF-00299804 in tablet form until progressive disease and then the maximum tolerated combined dose of PF-02341066 (given by mouth twice a day in tablet form) and PF-00299804 (given by mouth once a day in tablet form).
Drug: PF-02341066/PF-00299804
Combined PF-02341066 and PF-00299804
Drug: PF-02341066/PF-00299804
Single Agent PF-00299804 followed by Combined PF-02341066 and PF-00299804

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator s study team before subjects are included in the study.
  • Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
  • Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
  • Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
  • Disease Criteria:
  • Dose Escalation Phase: Histologically proven diagnosis of NSCLC that is locally advanced or metastatic, after failure of either at least one prior chemotherapy regimen or targeted therapy.
  • Expansion Phase: Histologically proven diagnosis of NSCLC that is locally advanced or metastatic and with acquired resistance to erlotinib or gefitinib. Acquired resistance is defined as progression following either an initial response (complete or partial), or stable disease for at least six months, while on single agent erlotinib or single agent gefitinib. In addition to these patients, Cohort 2 will also enroll patients from ongoing trials, including A7471017 and A7471028, who have progressed on single agent PF-00299804.
  • For the dose escalation phase, any prior treatment (chemotherapy, targeted therapy, radiation or surgery) must have been completed at least 2 weeks prior to initiation of study medication, except patients being treated with single agent PF-02341066 will have the option of continuing single agent PF-02341066 until the combination of PF- 02341066 and PF-00299804 is given. For the expansion phase, patients must not have had any intervening treatmen (chemotherapy, targeted therapy, radiation or surgery) between single agent erlotinib or single agent gefitinib treatment, and biopsy and dosing with study drug, unless agreed by the sponsor. In Expansion Cohort 2, patients who have received PF-00299804 as part of an ongoing clinical trial will continue with single agent therapy with PF-00299804 at their current dose after documentation of progression until the combination is given.
  • Any acute toxicity from prior treatment must have been recovered to less than or equal to Grade 1 (except alopecia).
  • At least 1 target lesion used for assessment of antitumor activity must be measurable by RECIST (version 1.1), or considered evaluable by agreement between the investigator and the sponsor.
  • Target lesions can be chosen from a previous irradiated area if lesions in those areas have documented progression.
  • Female or male, 18 years of age or older.
  • ECOG (Zubrod) performance status 0-2.
  • Adequate organ function as defined by the following criteria measured within 7 days prior to enrollment.
  • Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) less than or equal to 2.5 times upper limit of normal (ULN), or AST and ALT less than or equal to 5 times ULN if liver function abnormalities are due to underlying malignancy;
  • Total serum bilirubin less than or equal to 1.5 times ULN (except patients with documented Gilbert s syndrome);
  • Absolute neutrophil count (ANC) greater than or equal to1000/microL;
  • Platelets greater than or equal to 30,000/microL;
  • Hemoglobin greater than or equal to 8.0 g/dl;
  • Serum creatinine < 2 times institution ULN.
  • Adequate cardiac function, including:
  • 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention;
  • QTc interval less than or equal to 470 msec and without history of Torsades de Pointes or other symptomatic QTc abnormality;
  • LVEF (by MUGA or echocardiogram) of greater than or equal to 50%.
  • All female patients of child-bearing potential are required to have a negative pregnancy test at screening. The test should be repeated whenever one menstrual cycle is missed during treatment or a potential pregnancy is otherwise suspected.
  • Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, other study procedures and, for enrollment into the Expansion Phase, must be willing to undergo a tumor biopsy.

EXCLUSION CRITERIA:

Subjects presenting with any of the following will not be included in the study:

  • Participation in other studies or treatment within 2 weeks before the current study begins and/or during study participation (with the exception of patients who are receiving single agent PF-00299804 and who enroll into Expansion Cohort 2 from ongoing trials including A7471017 and A7471028, and with the exception of patients being treated with single agent PF-02341066 treatment who enroll during the dose escalation phase and exercise the option of continuing single agent PF-02341066 treatment until the combination of PF-02341066 and PF-00299804 is given) to allow for recovery and drug wash-out.
  • Known interstitial fibrosis or interstitial lung disease.
  • Patients with known brain metastases who are neurologically stable (asymptomatic) for at least 2 weeks and with no ongoing requirement for corticosteroids may enroll on study before treatment of brain metastases.
  • History of carcinomatous meningitis, or leptomeningeal disease.
  • Any of the following within 6 months prior to starting study treatment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident including transient ischemic attack.
  • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes). Diagnosed or suspected congenital long QT syndrome. Ongoing cardiac dysrhythmias of Grade greater than or equal to 2 (CTCAE version 4.02), uncontrolled atrial fibrillation of any grade, or QTc interval > 470 msec.
  • Hypertension that cannot be controlled by medications (> 150/100 mmHg despite optimal medical therapy).
  • Patient must not have had major surgery or trauma within 28 days prior to enrollment.
  • Active uncontrolled infection.
  • Pregnant or lactating females.
  • Significant gastrointestinal condition that may impair intake, transit, absorption or ability to tolerate investigational drugs.
  • Prior malignancy (other than NSCLC): patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or in situ cervical cancer, or localized and presumed cured prostate cancer with PSA < ULN) within the last 3 years.
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
  • Use of drugs or foods that are known potent CYP3A4 inhibitors within 7 days prior to the first dose of study medication, including but not limited to itraconazole, ketoconazole, miconazole, clarithromycin, erythromycin, indinavir, nefazodone, amprenavir, delavirdine, nelfinavir, ritonavir, saquinavir, diltiazem, verapamil and grapefruit juice.
  • Use of drugs that are known potent CYP3A4 inducers within 12 days prior to the first dose of study medication, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifabutin, rifampin, tipranavir, ritonavir, and St. John s wort.
  • Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to pimozide, aripiprazole, triazolam, ergotamine and halofantrine.
  • Concurrent use of drug that are highly dependent on CYP2D6 metabolism including S-metoprolol, propafenone, timolol, amitriptyline, clomipramine, desipramine, imipramine, paroxetine, haloperidol, risperidone, thioridazine, codeine, flecainide, mexilletine, tamoxifen, venlafaxine.

Dextromethorphan, a CYP2D6, substrate is allowed if medically indicated and no suitable alternative anti-tussive medication is available. However, the dose of dextromethorphan may need to be modified. In a clinical study in healthy volunteers who were extensive metabolizers (A7471039) PF-00299804 increased mean total exposure (AUC(last) and C(max)) of dextromethorphan 855% and 874%, respectively, following concomitant administration with PF-00299804 45 mg compared to exposure of administration of dextromethorphan alone. Extensive metabolizers comprise approximately 80% of the population, with ultra-, intermediate-, and poor-metabolizers accounting for the remaining portion of the general population. Therefore, if no alternative is available dextromethorphan dosing should be initiated at a lower dose (approx 25%) with close monitoring of patient clinical status. Dose increases or decreases of dextromethorphan may be considered based upon individual patient tolerability.

Lidocaine may be used systemically with clinical monitoring (including telemetry).

Opiates such as morphine, oxycodone, dihydrocodeine, hydrocodone, and tramadol can be used as substitutes to replace codeine. Use of these opiates should be monitored for altered analgesic effect during treatment as they may be partly metabolized by CYP2D6.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01441128

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Arun Rajan, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01441128     History of Changes
Other Study ID Numbers: 110250, 11-C-0250
Study First Received: September 24, 2011
Last Updated: August 23, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Lung Neoplasms
Epithelial-Mesenchymal Transition Factor (c-Met)
Tyrosine Kinase Inhibitor
Hepatocyte Growth Factor Receptor
Epidermal Growth Factor Receptor
Non Small Cell Lung Cancer
NSCLC

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Adenocarcinoma
Carcinoma
Carcinoma, Squamous Cell
Carcinoma, Large Cell
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Crizotinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014