Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)

NCT03087448 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: 166512NCI-2017-01318
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

Brief Summary

This is a phase I/II study of ceritinib and trametinib in Stage IIIB or IV anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). The Phase I portion will investigate the safety and tolerability of the combination of ceritinib and trametinib in ALK or ROS-1 rearranged NSCLC. The Phase II portion will investigate the clinical efficiency of the combination of ceritinib and trametinib in 3 single arm cohorts: ALKi (ALK inhibitor) naïve patients; post-crizotinib progressed disease (PD) patients; and PD second line ALK tyrosine kinase inhibitor (TKI) patients.

Conditions

Non-small Cell Lung Cancer

Keywords

ALK rearranged; Stage IIIB NSCLC; Stage IV NSCLC; ROS-1 rearranged NSCLC

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose (MTD)

  Determine the maximum tolerated dose (MTD) by evaluating the number and frequency of Adverse Events (AEs) as determined by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0 by investigator assessment, and identify a recommended phase II dose (RP2D) for phase II dose expansion cohorts.

  Up to 12 weeks.

Secondary Outcomes (6)

• Overall response rate (ORR)

  Up to 1 year

• Disease control rate (DCR)

  Up to 1 year

• Median Progression-free survival (PFS)

  Up to 2 years

• Median Overall survival (OS)

  Up to 18 months

• Time to central nervous system (CNS) progression

  Up to 1 year

Study Arms (1)

Ceritinib + Trametinib

EXPERIMENTAL

PHASE 1 Standard 3+3 dose escalation starting at dose level 1. Patients with ALK-rearranged, or ROS-1 rearranged NSCLC. 6-18 patients will be enrolled. Ceritinib dose: 300-450mg orally, once daily over 28 day cycles. Trametinib dose: 1.5mg-2.0mg orally, once daily over 28 day cycles. PHASE II The study was terminated before Phase II was initiated. The study did not open Phase II for enrollment.

Drug: Ceritinib; Drug: Trametinib

Interventions

Ceritinib DRUG

ALK tyrosine inhibitor, 300 mg - 450 mg PO daily. Phase I dose escalation: 1. Ceritinib 300mg 2. Ceritinib 450mg 3. Ceritinib 450mg The Phase II doses will be determined by Phase I dose escalation study

Also known as: Zykadia

Ceritinib + Trametinib

Trametinib DRUG

MEK kinase inhibitor, 1.5 mg - 2.0 mg PO daily. Phase I dose escalation: 1. Trametinib 1.5mg 2. Trametinib 1.5mg 3. Trametinib 2.0mg The Phase II doses will be determined by Phase I dose escalation study

Also known as: Mekinist

Ceritinib + Trametinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years old or older.
• Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
• Women of childbearing potential must have a negative serum pregnancy test within 3 days prior to Cycle 1 Day 1 and agree to use effective contraception, throughout the treatment period, and for 4 months after the last dose of study treatment.
• Patients must have histologically or cytological confirmed stage IIIB or IV non-small cell lung cancer.
• Documented ALK-rearrangement (or ROS1 rearrangement for phase I only) break-apart fluorescence in situ hybridization (FISH) (in at least 15% of tumor cells), or next generation sequencing assay performed on tumor sample or cell-free DNA in Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory.
• Measurable disease defined by RECIST 1.1 criteria
• Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2.
• Life expectancy of at least 3 months.
• Resolution of all acute toxic effects of prior chemotherapy, immunotherapy, radiotherapy or surgical procedures to ≤ grade 2 (CTCAE v 4.0). Exception to this criterion: patients with any grade of alopecia are allowed to enter the treatment.
• The following laboratory criteria have been met:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Hemoglobin (Hgb) ≥ 9 g/dL
• Platelets ≥ 75 x 109/L
• Prothrombin time (PT) / international normalized ratio (INR) and Partial thromboplastin time (PTT) ≤1.5 x upper limit of normal (ULN)
• Serum creatinine ≤ 1.5 mg/dL and /or calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 30 mL/min

You may not qualify if:

• Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
• Patient has history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
• Patient who has received thoracic radiotherapy to lung fields ≤4 weeks prior to starting the study treatment or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs) radiotherapy ≤2 weeks prior to starting the study treatment or has not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤2 weeks prior to starting study treatment is allowed.
• Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) within the last 3 weeks, or chemotherapy without delayed toxicity within the last 2 weeks preceding the first dose of the combination. Prior systemic treatment in the adjuvant setting is allowed.
• Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:
• unstable angina within 6 months prior to screening;
• myocardial infarction within 6 months prior to screening;
• history of documented congestive heart failure (New York Heart Association functional classification III-IV);
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication
• initiation or adjustment of antihypertensive medication(s) is allowed prior to screening;
• ventricular arrhythmias
• supraventricular and nodal arrhythmias not controlled with medication;
• other cardiac arrhythmia not controlled with medication;
• corrected QT (QTcF) \> 470 ms using Fridericia's correction on the screening electrocardiogram (ECG)
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of orally administered medication (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).

Sponsors & Collaborators

• University of California, San Francisco: lead
• Novartis Pharmaceuticals: collaborator
• University of California, Davis: collaborator

Study Sites (2)

University of California, Davis

Davis, California, 95616, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (1)

• Lara MS, Gubens MA, Bacaltos B, Daran L, Lim SL, Li T, Gandara DR, Bivona TG, Riess JW, Blakely CM. Phase 1 Study of Ceritinib Combined With Trametinib in Patients With Advanced ALK- or ROS1-Positive NSCLC. JTO Clin Res Rep. 2022 Nov 21;3(12):100436. doi: 10.1016/j.jtocrr.2022.100436. eCollection 2022 Dec.

  PMID: 36545322 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

ceritinib; trametinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Collin Blakely, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2017
• First Posted: March 22, 2017
• Study Start: September 9, 2017
• Primary Completion: April 30, 2022
• Study Completion: April 30, 2022
• Last Updated: December 27, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)