A Study of the Combination of Osimertinib, Platinum and Etoposide for Patients With Metastatic EGFR Mutant Lung Cancers

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03567642

Collaborator

(none)

Enrollment

Locations

Arm

71.7

Anticipated Duration (Months)

2.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to test the safety of combining Osimertinib with either Cisplatin or Carboplatin (at different dose levels) and Etoposide, to find out what effects, if any, this combination of drugs has on people with EGFR mutant lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Drug: Osimertinib Drug: Platinum Drug: Etoposide	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 1 Study of Combination Osimertinib, Platinum, Etoposide for Patients With Metastatic EGFR Mutant Lung Cancers With Concurrent RB1 and TP53 Alterations

Actual Study Start Date :

Jun 12, 2018

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Osimertinib, Platinum (cisplatin or carboplatin) and Etoposide Initially, 6 patients will be enrolled and will begin treatment with osimertinib 80mg orally daily (3 who will be receiving cisplatin and 3 who will be receiving carboplatin). Cisplatin or carboplatin treatment will be decided by the treating physician prior to study registration. After 9 weeks (+/- 1 week)( 3 cycles) on osimertinib alone, carboplatin or cisplatin and etoposide will be added. Carboplatin is doses at an AUC of 5 or cisplatin at 60mg/m2 will be given on C4D1. Etoposide is dosed at 100mg/m2 given on Days 1-3 of C4. Only patients on osimertinib 80mg orally daily at the start of cycle 4 will be included in the 3+3 dose de-escalation portion of the study. Chemotherapy and osimertinib will be administered concurrently during cycles 4-7, and from cycle 8 onward, osimertinib monotherapy will be continued. Patients will present every 2 cycles post-chemo (Cycles 8, 10, 12, etc.)	Drug: Osimertinib Osimertinib 80mg daily Drug: Platinum Cisplatin 60mg/m2 or Cisplatin 45mg/m2 Carboplatin AUC 5 or Carboplatin AUC 4 Drug: Etoposide Etoposide 100mg/m2 or Etoposide 80mg/m2

Arm

Intervention/Treatment

Experimental: Osimertinib, Platinum (cisplatin or carboplatin) and Etoposide

Initially, 6 patients will be enrolled and will begin treatment with osimertinib 80mg orally daily (3 who will be receiving cisplatin and 3 who will be receiving carboplatin). Cisplatin or carboplatin treatment will be decided by the treating physician prior to study registration. After 9 weeks (+/- 1 week)( 3 cycles) on osimertinib alone, carboplatin or cisplatin and etoposide will be added. Carboplatin is doses at an AUC of 5 or cisplatin at 60mg/m2 will be given on C4D1. Etoposide is dosed at 100mg/m2 given on Days 1-3 of C4. Only patients on osimertinib 80mg orally daily at the start of cycle 4 will be included in the 3+3 dose de-escalation portion of the study. Chemotherapy and osimertinib will be administered concurrently during cycles 4-7, and from cycle 8 onward, osimertinib monotherapy will be continued. Patients will present every 2 cycles post-chemo (Cycles 8, 10, 12, etc.)

Drug: Osimertinib

Osimertinib 80mg daily

Drug: Platinum

Cisplatin 60mg/m2 or Cisplatin 45mg/m2 Carboplatin AUC 5 or Carboplatin AUC 4

Drug: Etoposide

Etoposide 100mg/m2 or Etoposide 80mg/m2

Outcome Measures

Primary Outcome Measures

The MTD (maximum tolerated dose) [2 years]
Determine the safety and toxicity profile of combination osimertinib, platinum (cisplatin or carboplatin), etoposide for patients with metastatic EGFR mutant lung cancers with concurrent RB1 and TP53 alterations.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent
Advanced biopsy-proven metastatic non-small cell lung cancer
Either have not started an EGFR TKI or may have started osimertinib within the last 9 weeks
Somatic activating mutation in EGFR in pre-treatment tumor biopsy or cfDNA
Evidence of a concurrent P53 alteration by IHC or NGS on pre-treatment tumor biopsy or cfDNA
Evidence of a concurrent RB1 alteration by IHC or NGS on pre-treatment tumor biopsy or cfDNA
Must have a site of disease amenable to repeat biopsy and be willing to undergo a biopsy during treatment
Measurable (RECIST 1.1) indicator lesion not previously irradiated
Karnofsky performance status (KPS) ≥ 70%
Age >18 years old
Ability to swallow oral medication
Adequate organ function
AST, ALT ≤ 3 x ULN
Total bilirubin ≤ 1.5x ULN
Creatinine ≤ 1.5x ULN OR calculated creatinine clearance ≥ 60ml/min
Absolute neutrophil count (ANC) ≥ 1000 cells/mm^3
Hemoglobin≥8.0 g/dL
Platelets ≥100,000/mm^3

Exclusion Criteria:

Pregnant or lactating women
Started an EGFR TKI other than osimertinib or started osimertinib more than 9 weeks ago
Any radiotherapy within 1 week of starting treatment on protocol.
Any major surgery within 1 weeks of starting treatment on protocol.
Any evidence of active clinically significant interstitial lung disease
Continue to have unresolved > grade 1 toxicity from any previous treatment
Have pure small cell histology
Corrected QT interval using Fridericia's formula (QTcF)>475msec or any clinically significant (as deemed by the investigator) abnormalities in rhythm or conduction or morphology of the resting EKG.
Patients are to be excluded from cisplatin treatment arm if they meet any of the following criteria:
Creatinine clearance < 60 ml/min
Hearing impairment requiring assistive device
Neuropathy
The treating provider does not feel as though the patient should receive cisplatin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memoral Sloan Kettering Cancer Center	Basking Ridge	New Jersey	United States	07920
2	Memorial Sloan Kettering Monmouth	Middletown	New Jersey	United States	07748
3	Memorial Sloan Kettering Bergen	Montvale	New Jersey	United States	07645
4	Memorial Sloan Kettering Commack	Commack	New York	United States	11725
5	Memorial Sloan Kettering Westchester	Harrison	New York	United States	10604
6	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
7	Memorial Sloan Kettering Nassau	Uniondale	New York	United States	11553