Clinical trial NCT01526928: Study to Evaluate Safety, Pharmacokinetics, and Efficacy of Rociletinib (CO-1686) in Previously Treated Mutant Epidermal Growth Factor Receptor (EGFR) in Non-Small Cell Lung Cancer (NSCLC) Patients
Official title: A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Locally Advanced or Metastatic Non Small Cell Lung Cancer
Keywords: cancer
metastatic
locally advanced
lung
non-small cell lung cancer
NSCLC
epidermal growth factor receptor
EGFR
T790M
CO-1686
unresectable
recurrent
EGFR-directed therapy
irreversible EGFR inhibitor
TIGER
Rociletinib
Lead sponsor: Clovis Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2012-02-06
Enrollment: 612
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Rociletinib is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation.

Detailed description: Lung cancer remains the most common cancer worldwide with non-small cell lung cancer accounting for 85% of cases. Cytotoxic chemotherapy has been the mainstay of patients with NSCLC; however, survival rates remain low and toxicity is significant. Molecularly targeted therapies have proven to be superior to chemotherapy for NSCLC patients whose tumors have mutations in EGFR. Recent studies have established tyrosine kinase inhibitors (TKIs) as the gold standard for treating EGFR-mutation-positive NCSLC. However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. There are currently no approved therapies for patients who progress on TKIs. Rociletinib may provide an effective therapy for a patient population with few alternative treatment options. Nonclinical data demonstrate that rociletinib inhibits T790M. It is anticipated that rociletinib may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to first generation TKIs.

This is a two-part, open-label study of oral rociletinib administered daily in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as erlotinib, gefitinib or afatinib.

This study will include 2 parts:

Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22

Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have:

Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test

Eligibility criteria: Inclusion Criteria -

All patients must meet the following inclusion criteria:

1. Metastatic or unresectable locally advanced NSCLC
2. Evidence of a tumor with one or more EGFR mutations excluding exon 20 insertion
3. Biopsy of either primary or metastatic tumor tissue within 60 days of dosing
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
5. Minimum age of 18 years
6. Adequate hematological and biological function
7. Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study-specific evaluation

Phase 2 Cohorts must also meet the following inclusion criteria:

* Disease progression confirmed by radiologic assessment while on treatment with EGFR- TKI Or
* Disease progression confirmed by radiologic assessment while on treatment with the first single agent EGFR TKI and
* Documented evidence of T790M mutation in EGFR following disease progression on the first single agent EGFR TKI.
* Measureable disease according to RECIST Version 1.1

Exclusion Criteria -

Any of the following criteria will exclude patients from study participation:

1. Documented evidence of an Exon 20 insertion activating mutation in the EGFR gene
2. Active second malignancy
3. Known pre-existing interstitial lung disease
4. Patients with Leptomeningeal carcinomatosis are excluded. Other CNS metastases are only permitted if treated, asymptomatic and stable (not requiring steroids for at least 4 weeks prior to start of study treatment).
5. Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib
6. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib
7. Prior treatment with rociletinib or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR
8. Certain cardiac abnormalities or history
9. Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib
10. Females who are pregnant or breastfeeding
11. Refusal to use adequate contraception for fertile patients (females and males) for 12 weeks after the last dose of rociletinib
12. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study
13. Any other reason the investigator considers the patient should not participate in the study

Primary outcomes:
measure: Percentage of T790M Positive Patients With Confirmed Response Per Investigator
timeFrame: Cycle 1 Day 1 to End of Treatment, up to approximately 42 months
measure: Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment
timeFrame: Cycle 1 Day 1 to End of Treatment, up to approximately 36 months
measure: Dose Limiting Toxicity (DLT) Incidence
timeFrame: Cycle 1 Day 1 to Cycle 1 Day 21
Secondary outcomes:
measure: Overall Survival (OS) Determined by Investigator Assessment
timeFrame: Cycle 1 Day 1 to date of death, assessed up to 42 months
measure: Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)
timeFrame: Cycle 1 Day 1 to End of Treatment, up to approximately 42 months
measure: PK Profile of Rociletinib - Cmax
timeFrame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
measure: PK Profile of Rociletinib - Tmax
timeFrame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
measure: PK Profile of Rociletinib - AUC 0-24
timeFrame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
measure: PK Profile of Rociletinib - T 1/2
timeFrame: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
measure: Food Effect on PK of Rociletinib - Cmax
timeFrame: Day -7 prior to Cycle 1 Day 1, or approximately 7 days
measure: Food Effect on PK of Rociletinib - Tmax
timeFrame: Day -7 prior to Cycle 1 Day 1, or approximately 7 days
measure: Food Effect on PK of Rociletinib - AUC 0-24
timeFrame: Day -7 prior to Cycle 1 Day 1, or approximately 7 days
measure: Food Effect on PK of Rociletinib - C24
timeFrame: Day -7 prior to Cycle 1 Day 1, or approximately 7 days
measure: Food Effect on PK of Rociletinib - T 1/2
timeFrame: Day -7 prior to Cycle 1 Day 1, or approximately 7 days
measure: QTcF Values Post Baseline by Daily Dose
timeFrame: Screening to End of Treatment, up to approximately 42 months
measure: QTcF Value Change From Baseline
timeFrame: Screening to End of Treatment, up to approximately 42 months
measure: Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR
timeFrame: Cycle 1 Day 1 to End of Treatment / End of Follow-up
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Fountain Valley
country: United States
facility: Compassionate Care Research Group, Inc.
state: California
city: Los Angeles
country: United States
facility: University of Southern California, Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Samuel Oschin Cancer Center
state: California
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Santa Monica
country: United States
facility: UCLA Health System
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Whittier
country: United States
facility: East Valley Hematology and Oncology Medical Group, Inc.
state: California
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovations
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center/UMHC
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute
state: Florida
city: Athens
country: United States
facility: University Cancer & Blood Center
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center, The Duchossois Center for Advanced Medicine
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Mass General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Care Institute
state: Michigan
city: Morristown
country: United States
facility: Regional Cancer Care Associates
state: New Jersey
city: New Brunswick
country: United States
facility: Regional Cancer Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Lake Success
country: United States
facility: Monter Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University, Comprehensive Cancer Center
state: Ohio
city: Tulsa
country: United States
facility: Tulsa Cancer Institute
state: Oklahoma
city: Portland
country: United States
facility: Providence CancerCenter Oncology and Hematology Care Clinic-Eastside Portland
state: Oregon
city: Philadelphia
country: United States
facility: Perelman Center for Advanced Medicine
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPMC), Div. of Medical Oncology
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
city: Nice Cedex 2
country: France
facility: Centre Antoine Lacassagne
state: Provence Alpes COTE D'azur
city: Grenoble Cedex 9
country: France
facility: Centre Hospitalier Universitaire de Grenoble
state: Rhone-alpes
city: Lyon Cedex 04
country: France
facility: Centre Léon Bérard
state: Rhone-alpes
city: Caen Cedex 05
country: France
facility: Centre François Baclesse
city: Creteil cedex
country: France
facility: Centre Hospitalier Intercommunal Créteil
city: Lille
country: France
facility: Centre Hospitalier Régional Universitaire de Lille
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Gdansk
country: Poland
facility: Med University Gdansk
Study officials:
References:
citation: Krug AK, Enderle D, Karlovich C, Priewasser T, Bentink S, Spiel A, Brinkmann K, Emenegger J, Grimm DG, Castellanos-Rizaldos E, Goldman JW, Sequist LV, Soria JC, Camidge DR, Gadgeel SM, Wakelee HA, Raponi M, Noerholm M, Skog J. Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma. Ann Oncol. 2018 Mar 1;29(3):700-706. doi: 10.1093/annonc/mdx765.
citation: Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, Papadimitrakopoulou V, Solomon BJ, Oxnard GR, Dziadziuszko R, Aisner DL, Doebele RC, Galasso C, Garon EB, Heist RS, Logan J, Neal JW, Mendenhall MA, Nichols S, Piotrowska Z, Wozniak AJ, Raponi M, Karlovich CA, Jaw-Tsai S, Isaacson J, Despain D, Matheny SL, Rolfe L, Allen AR, Camidge DR. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1700-9. doi: 10.1056/NEJMoa1413654.