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Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M)

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ClinicalTrials.gov Identifier: NCT02349633
Recruitment Status : Active, not recruiting
First Posted : January 29, 2015
Last Update Posted : December 17, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:

This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below:

  • Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC,
  • Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and
  • Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M).

Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Drug: PF-06747775 Drug: Palbociclib Drug: Avelumab Phase 2

Detailed Description:
There remains an unmet medical need to develop EGFR TKI agents that effectively target both the single activating mutations of del 19 and L858R, and the secondary resistance mutation T790M, while sparing WT EGFR. Drugs active against the resistance mutation will enable molecularly targeted therapy with a more favorable toxicity profile than the current standard of cytotoxic chemotherapy platinum based doublets. Furthermore, by having a wide margin of selectivity favoring the EGFR mutants versus WT EGFR, PF 06747775 is likely to be positioned to improve patient outcomes from an efficacy and safety perspective.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Allocation: Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Open-label Study Of Pf-06747775 (Epidermal Growth Factor Receptor T790m Inhibitor) In Patients With Advanced Epidermal Growth Factor Receptor Mutant (Del 19 Or L858r ± T790m) Non-small Cell Lung Cancer
Actual Study Start Date : May 14, 2015
Estimated Primary Completion Date : December 2, 2019
Estimated Study Completion Date : March 15, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1
Cohort 1 will be initiated (current dose 200 mg)
Drug: PF-06747775
Experimental: Cohort 2A
Cohort 2A will evaluate PF-06747775 200 mg by mouth (PO) daily (QD) in combination with palbociclib continuous PO QD dosing in 21-day cycles. The starting dose (DL1) for palbociclib will be 100 mg PO daily. Dose finding will follow mTPI method with adjustments using DLT rate.
Drug: PF-06747775
Drug: Palbociclib
Experimental: Cohort 2B
Cohort 2B will be initiated once the RP2D of the PF-06747775 and palbociclib combination is determined.
Drug: PF-06747775
Drug: Palbociclib
Experimental: Cohort 3
Cohort 3 combination is PF-06747775 200 mg PO QD and avelumab 10 mg/kg IV Q2W in 28-day (4-week) cycles. Dose finding will follow the mTPI design. Once RP2D of PF-06747775 in combination with avelumab is determined, the Dose Expansion Phase will be opened.
Drug: PF-06747775
Drug: Avelumab



Primary Outcome Measures :
  1. Phase 1 Primary Endpoint - Number of patients with dose limiting toxicities during Phase 1 [ Time Frame: 21 days ]
    The target probability of DLT at MTD will be 30%

  2. Phase 1b/2 - Cohort 1 = confirmed OR per RECIST; Cohort 2A = Cycle 2 DLT; Cohort 2B = PFS and Cohort 3 = Cycle 1 DLT [ Time Frame: Cohorts 1, 2A and 2B = 21 day cycles and Cohort 3 = 28 day cycles ]

    Cohort 1 is an evaluation of PF 06747775 single agent at RP2D Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either palbociclib or avelumab, respectively, based on safety and tolerability.

    Determination of the RP2D will be performed using the mTPI design. For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib combination, a randomized evaluation of the combination vs PF-06747775 single agent (2:1 ratio) will be initiated (Cohort 2B). For Cohort 3, after determination of the RP2D for the PF-06747775 and avelumab combination, the dose level will be expanded to enroll an overall total of approximately 20 patients to further explore the safety, PK, and antitumor activity of the combination.



Secondary Outcome Measures :
  1. Phase 1: Secondary Endpoint - Number of patients with Objective Response (OR) [ Time Frame: Time from first dose of study drug until OR of CR or PR up to 24 months ]
    Number of patients with OR based assessment of confirmed CR or PR according to RECIST. CR are those that persist on repeat imaging at least 4 weeks after the initial documentation of response. PR are those that are greater or equal to a 30% decrease ( per RECIST) under the baseline of the sum of diameters of all target measurable disease

  2. Phase 1b/2 [ Time Frame: Time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months ]
    PFS (cohort 1, 2A and 3) ORR (cohort 2A, 2B and 3) DOR (All cohorts)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Partial Inclusion criteria:

Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del 19 or L858R) NSCLC:

  1. As detected by local EGFR mutation test that includes QIAGEN therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory (with tissue submitted for central laboratory confirmation via FDA approved QIAGEN therascreen RCQ PCR kit).
  2. T790M disease as follows:

    Phase 1 If a repeat biopsy was performed on the tumor following prior EGFR TKI therapy, then T790M positive disease must be present. Patients of unknown T790M status following EGFR TKI progression (ie, no post EGFR TKI progression biopsy was performed) are eligible.

    In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm (del 19 or L858R) with any T790M status are eligible to enroll.

    Studies at RP2D Cohort 1: Patients may have de novo T790M mutation, but it is not required. Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor.

  3. Prior treatment for EGFRm NSCLC as follows:

Phase 1 Has progressed after at least 1 prior line of therapy including and EGFR TKI. Patients may have also received other lines of therapy before or after the EGFR TKI.

Studies at RP2D Cohort 1: no prior treatment for locally advanced or metastatic EGFRm NSCLC. Cohorts 2 and 3: must have had disease progression on treatment with an approved 1st or 2nd generation EGFR TKI. Patients who have been treated with a 3rd generation EGFR TKI are ineligible for this study. Patients may have had multiple lines of therapy; however, the last therapy prior to study treatment must have been an approved EGFR TKI and received within 6 weeks prior to study registration.

Patients must have at least one measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated.

Tumor tissue available. Requesting formalin fixed paraffin embedded (FFPE) block or 15 unstained sections (5 micron). If a lesser amount of tissue is available, contact the sponsor. An archival specimen is acceptable for Phase 1; a de novo specimen is required for Cohorts 2, and 3 if the T790M status was confirmed by tissue biopsy.

Partial Exclusion Criteria:

For All Phases/Cohorts Previously diagnosed brain metastases, unless the patient has completed the treatment that is clinically indicated, if any, and has recovered from the acute effects of any treatment that was delivered prior to study registration, have discontinued corticosteroid treatment for these metastases prior to registration, and are neurologically stable.

Major surgery within 2 weeks prior to registration.

Radiation therapy, excluding stereotactic radiosurgery (SRS), within 1 week prior to registration.

Systemic anti cancer therapy within 2 weeks or 5 half-lives (whichever is longer) of registration excluding EGFR TKIs. Patients on EGFR TKIs must discontinue the agent for a minimum of:

  • 2 days prior to registration for erlotinib or afatinib, or 3 days for gefitinib if they will be part of the lead-in single dose PF-06747775 PK study (Phase 1 Dose Escalation Single and Multiple dose PK and ECG Assessments; Phase 1 Sildenafil at MTD; and Phase 1b/2 First-Line Single Agent). Please contact the Sponsor for direction for any other EGFR TKI.
  • 5 half-lives or 5 days (whichever is longer) prior to registration if they will be starting on continuous PF-06747775 dosing directly (Phase 1 PK sub-studies at RP2D; Phase 1b/2 Combination with Palbociclib; Phase 1b Combination with Avelumab).

Partial Exclusions for Cohort 2A and 2B (Palbociclib combo):

Prior treatment with a CDK 4/6 inhibitor.

Partial Exclusions for Cohort 3 (Avelumab combo):

Prior therapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti cytotoxic T lymphocyte associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways).

Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible

Use of immunosuppressive medication at time of randomization


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02349633


Locations
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United States, California
UC San Diego Moores Cancer Center - Investigational Drug Services
La Jolla, California, United States, 92037-0845
UC San Diego Medical Center - La Jolla
La Jolla, California, United States, 92037
UC San Diego Moores Cancer Center
La Jolla, California, United States, 92093-0698
UC San Diego Medical Center - Hillcrest
San Diego, California, United States, 92103
United States, Connecticut
Smilow Cancer Hospital at Yale-New Haven
New Haven, Connecticut, United States, 06510
United States, Pennsylvania
Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15232
UPMC Cancer Pavilion
Pittsburgh, Pennsylvania, United States, 15232
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15232
United States, Washington
Seattle Cancer Care Alliance
Seattle, Washington, United States, 98109
University of Washington Medical Center
Seattle, Washington, United States, 98195
Australia, New South Wales
Chris O'Brien Lifehouse
Camperdown, New South Wales, Australia, 2050
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia, 2050
Australia, Queensland
Prince Charles Hospital, Cancer Care Services
Chermside, Queensland, Australia, 4032
Japan
National Hospital Organization Shikoku Cancer Center
Matsuyama, Ehime, Japan, 791-0280
The Cancer Institute Hospital of JFCR
Koto-ku, Tokyo, Japan, 135-8550
Korea, Republic of
Seoul National University Hospital / Department of Internal Medicine
Seoul, Korea, Republic of, 03080
Severance Hospital, Yonsei University Health System
Seoul, Korea, Republic of, 03722
Asan Medical Center
Seoul, Korea, Republic of, 05505
Clinical Trial Pharmacy
Seoul, Korea, Republic of, 05505
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02349633     History of Changes
Other Study ID Numbers: B7971001
First Posted: January 29, 2015    Key Record Dates
Last Update Posted: December 17, 2018
Last Verified: December 2018

Keywords provided by Pfizer:
EGFRm - Epidermal Growth Factor Receptor Mutation
Advanced EGFRm (del19 or L858R +/- T790M NSCLC

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Mitogens
Palbociclib
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors