Low Dose Daily Erlotinib in Combination With High Dose Twice Weekly Erlotinib in Patients With EGFR-Mutant Lung Cancer

A Phase 1 Trial of Low Dose Daily Erlotinib in Combination With High Dose Twice Weekly Erlotinib in Patients With EGFR-Mutant Lung Cancer

The purpose of this study is to test the safety of different ways of taking erlotinib. The investigators want to find out what effects, good and/or bad, combination daily low dose and twice weekly high dose erlotinib has on the patient and lung cancer. The investigators are also seeing whether different schedules of erlotinib are better at treating lung cancer that has spread to the central nervous system.

CNS expansion phase:

The pulse continuous regimen will be then assess in patients with EGFR mutant lung cancers and CNS involvement. An additional expansion cohort (A) will enroll 19 patients with newly diagnosed EGFR mutant lung cancer with CNS involvement at diagnosis. The patients in the expansion cohorts will undergo the same treatment plan as the patients in the dose expansion cohort. A patient in the expansion cohorts will not be replaced if he/she does not finish the first 28 day (cycle 1) treatment period.

Study Overview

• Status: Completed
• Conditions: EGFR-Mutant Lung Cancer
• Intervention / Treatment: Drug: erlotinib

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Basking Ridge, New Jersey, United States
      • Memoral Sloan Kettering Cancer Center
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Commack
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • Rockville Centre, New York, United States, 11570
      • Memorial Sloan Kettering Rockville Centre
    • Sleepy Hollow, New York, United States, 10591
      • Memoral Sloan Kettering Cancer Center at Phelps

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• MSKCC pathologically-proven diagnosis locally advanced Stage III not amenable to definitive, curative treatment or Stage IV or recurrent non-small cell lung cancer
• Documented presence of EGFR mutation confirmed by MSKCC or a local facility.
• No prior treatment with erlotinib, gefitinib, or other EGFR tyrosine kinase inhibitors
• Age ≥ 18 years
• Measurable (RECIST 1.1) indicator lesion not previously irradiated.
• Karnofsky Performance Status ≥ 70%
• Ability to take oral medications
• A negative serum pregnancy test obtained within 4 weeks prior to the start of treatment in all women of child-bearing potential.
• All women of child bearing potential and sexually active men must agree to use adequate methods of birth control throughout the study which includes use of oral contraceptives with an additional barrier methods, double barrier methods, Depo-Provera, permanent sterilization of patient or partner or total abstinence.

Expansion A:

• brain metastases or leptomeningeal not previously treated with radiation or surgery

Exclusion Criteria:

• Inadequate recovery from any toxicity related to prior treatment (to Grade 2 or baseline).
• Inadequate hematologic function defined as ANC < 1000 cells/mm³, Platelet count <75,000/mm³ or Hemoglobin <9.0g/dL.
• Inadequate hepatic function defined by AST/ALT >3x upper limit of normal (ULN), Total bilirubin>2x ULN, Alkaline phosphatase >3x ULN.
• Symptomatic brain metastasis requiring radiation therapy or escalating doses of steroids.
• Patients with clinically stable brain metastases or leptomeningeal disease (previously treated or untreated) are eligible. Patients in expansion cohort A must have at least one untreated CNS lesion
• Women who are breastfeeding or pregnant.
• Any evidence of clinically active interstitial lung disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: erlotinib; This protocol is a phase 1, single arm, open label study of combination daily low dose erlotinib plus twice weekly high dose erlotinib in patients with EGFR-Mutant lung cancer who have not yet received erlotinib or gefitinib. Six dose levels are planned for escalation, with the pulse dose erlotinib increasing. Expansion cohort A: Treat an additional 19 pts at the MTD with CNS involvement at diagnosis

Drug: erlotinib; Cycle 1, week 1 (D1-D7) will consist of pulse dose erlotinib on D1 & D2 without daily low dose erlotinib on D3-7. For all subsequent weeks, patients will take high dose erlotinib on D1 & D2, & will receive erlotinib 50 mg oral daily x 5 days on days 3-7. On days 1 & 2, patients will take one of the following doses of erlotinib, depending on the dose cohort they are enrolled in: Dose level 1 600 mg oral daily on D1, D2 Dose level 2 750 mg oral daily on D1, D2 Dose level 3 900 mg oral daily on D1, D2 Dose level 4 1050 mg oral daily on D1, D2. An additional Dose -1 (pulse dose erlotinib on D1, D2 with 25 mg oral daily x 5 days in D3-D7) will be reserved, in the unlikely situation that Dose 1 is proved too toxic. If Dose -1 is tolerated well (600mg oral daily D1, D2 & 25mg oral daily D3-D7), pulse dose escalation can continue as described above, with erlotinib at the daily low dose of 25 mg oral on D3-D7.; Other Names: The assigned dosing schedule will be repeated weekly x 3 to complete a 3 week; (21 day) cycle. Cycle 1 will be 4 weeks to account for one week of lead in; pulse dose erlotinib only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
to determine the maximum tolerated dose (MTD)	The study will use a standard 3+3 dose escalation design. Three to six patients will need to be enrolled at each dose level and assessed for DLT for 1 full cycle (28 days for cycle 1) before dose escalation decision is made.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
to evaluate the safety profile	Toxicity will be graded according to NCI CTCAE, version 4.0. The analysis of safety/tolerability data will be descriptive; toxicity events will be individually tabulated.	1 year
Progression Free Survival (PFS)	Progression free survival (PFS) is defined as the duration of time from first treatment to time of progression or death, whichever occurs first.	1 year
Response rate (RR)	sum of complete responses and partial responses according to RECIST 1.1	1 year
Overall survival (OS)	Overall survival (OS) is defined as the duration of time from first treatment to time of death.	1 year

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Astellas Pharma US, Inc.

Publications and helpful links

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2013
• Primary Completion (Actual): November 8, 2018
• Study Completion (Actual): November 8, 2018

Study Registration Dates

• First Submitted: October 15, 2013
• First Submitted That Met QC Criteria: October 17, 2013
• First Posted (Estimate): October 22, 2013

Study Record Updates

• Last Update Posted (Actual): November 13, 2018
• Last Update Submitted That Met QC Criteria: November 8, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Erlotinib; CNS involvement; 12-278
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: 12-278