Ceritinib (LDK378) for Patients Whose Tumors Have Aberrations in ALK or ROS1 (SIGNATURE) (SIGNATURE)

Modular Phase II Study to Link Targeted Therapy to Patients With Pathway Activated Tumors: Module - 7 Ceritinib (LDK378) for Patients Whose Tumors Have Aberrations in ALK or ROS1

The purpose of this signal seeking study was to determine whether treatment with ceritinib demonstrated sufficient efficacy in select pathway-activated solid tumors and/or hematologic malignancies to warrant further study.

Study Overview

• Status: Terminated
• Conditions: Tumors With Aberrations in ALK or ROS1
• Intervention / Treatment: Drug: Ceritinib

Detailed Description

This was an open label study to determine the efficacy and safety of treatment with ceritinib in patients with a diagnosis of solid tumors or hematological malignancies that had been pre-identified (prior to study consent) to have ALK or ROS1 positive mutations, translocations, rearrangements or amplifications and whose disease had progressed on or after standard treatment. The study consisted of a treatment phase where all patients received ceritinib capsules for a total dose of 750 mg daily for up to 8 cycles of 28 days. Disease assessments for clinical benefit were performed every 8 weeks until disease progression or end of treatment. Following discontinuation of treatment for any reason, patients were followed for safety for 30 days. Survival information was collected every 3 months until 2 years after the last patient had enrolled into the study. Study was amended to allow for discontinuation of survival period if primary endpoint was not met.

Study was terminated due to low enrollment.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Santa Rosa, California, United States, 94503
      • St Joseph Heritage Healthcare St. Joseph Heritage
  • Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon Research Institute
    • Greenwood Village, Colorado, United States
      • Rocky Mountain Cancer Centers Dept of Rocky Mountain (2)
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists Florida Cancer Specialists (31
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Northwestern (6)
  • Iowa
    • Cedar Rapids, Iowa, United States, 52403
      • Physicians Clinic of Iowa
  • Maryland
    • Silver Spring, Maryland, United States, 20910
      • Holy Cross Hospital Holy Cross (2)
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Southeast Nebraska Oncology
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Comprehensive Cancer Centers of Nevada CCC of Nevada (1)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center Seeley G. Mudd Bldg.
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health Health Sciences
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Hematology Oncology
  • Ohio
    • Columbus, Ohio, United States, 39705
      • Columbus Hematology and Oncology PA Columbus Hem and Onc (2)
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States, 17011
      • Andrew and Patel Associates
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital Rhode Island Hosp. (2)
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford University of South Dakota Medical Center Sanford Clinical Research
  • Texas
    • Houston, Texas, United States, 77024
      • Oncology Consultants Oncology Group
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center/University of Texas MD Anderson Cancer Center (3)
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists Utah Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute Swedish Cancer Institute
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Aurora Research Institute

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:

• Patient had a confirmed diagnosis of a select solid tumor (except ALK+ NSCLC) or hematological malignancy and was in need of treatment because of radiologic progression or relapse.
• Patient must have been pre-identified as having a tumor with an ALK or ROS1 positive mutation, translocation, rearrangement or amplification. The qualifying alteration must have been assessed and reported by a CLIA-certified laboratory. ALK positivity as assessed by IHC or FISH were allowed.
• Patient must have received at least one prior treatment for recurrent, metastatic and/or locally advanced disease and for whom no standard therapy options were anticipated to result in a durable remission.
• Patient had progressive and measurable disease as per RECIST 1.1 or other appropriate hematological guidelines.
• Patient had an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.

Exclusion Criteria:

• Patient had received prior treatment with ceritinib.
• Patients with symptomatic CNS metastases who were neurologically unstable or required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
• Patient had received chemotherapy or anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, monoclonal antibodies or mitomycin-C) prior to starting study drug.

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: Ceritinib 750 mg; Ceritinib was dosed on a flat scale of 750 mg (e.g., 5 x 150 mg capsules) orally, once daily, on a continuous dosing cycle. A complete treatment cycle was defined as 28 days with no breaks between dosing cycles.	Drug: Ceritinib; Ceritinib was dosed on a flat scale of 750 mg (e.g., 5 x 150 mg capsules) orally,once daily, on a continuous dosing cycle. A complete treatment cycle was defined as 28 days. There were no breaks between dosing cycles.; Other Names: LDK378

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) Utilizing RECIST 1.1 at Approximately 16 Weeks	Solid tumors were assessed using RECIST 1.1 criteria and included responses of complete response (CR) or partial response (PR) or stable disease (SD). For hematologic tumors, other hematological response criteria applied. CR=disappearance of all target lesions. Pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. PR=at least 30% decrease in sum of diameters of target lesions from baseline sum diameters. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive disease (PD)=at least a 20% increase in sum of diameter of measured target lesions from smallest sum of diameter of all target lesions recorded at or after baseline (sum must also demonstrate an absolute increase of at least 5mm). One or more new lesions was considered PD. Overall response rate (ORR) = (CR + PR). Clinical benefit rate = (CR + PR + SD)	Baseline up to approximately 16 weeks
Number of Participants With Tumor Responses Utilizing RECIST 1.1 at Approximately 16 Weeks	For patients with solid tumors the assessment criteria was RECIST 1.1 and included responses of complete response (CR) or partial response (PR) or stable disease (SD). For hematologic tumors, other hematological response criteria applied. CR=disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. PR=at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive disease (PD)=at least a 20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline (sum must also demonstrate an absolute increase of at least 5mm). One or more new lesions was also considered progression.	Baseline up to approximately 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Progression-free survival (PFS) was the time from the date of start of study drug to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a patient has not had an event, progression-free survival was censored at the date of last adequate tumor assessment.	Baseline up to approximately 27 months
Percentage of Participants With Progression-Free Survival (PFS) - Kaplan-Meier Estimates	Progression-free survival (PFS) was the time from the date of start of study drug to the date of event defined as the first documented progression or death due to any cause within 30 days of the last dose. If a patient has not had an event, progression-free survival was censored at the date of last adequate tumor assessment.	Basleline up to approximately 27 months
Overall Survival (OS) - Number of Participant Deaths	Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause	Baseline up to approximately 27 months
Duration of Response (DOR)	Duration of response (DOR) is defined as time from the first documented response (CR or PR) to the date first documented disease progression or relapse or death due to any cause	baseline up to approximately 30 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2014
• Primary Completion (Actual): December 13, 2017
• Study Completion (Actual): December 13, 2017

Study Registration Dates

• First Submitted: July 3, 2014
• First Submitted That Met QC Criteria: July 8, 2014
• First Posted (Estimate): July 10, 2014

Study Record Updates

• Last Update Posted (Actual): April 8, 2021
• Last Update Submitted That Met QC Criteria: March 12, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: NSCLC; mutation; B-cell lymphoma; ROS1; translocation; ALK; hematological malignancy; amplification; solid tumor malignancy; rearrangement
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ceritinib
• Other Study ID Numbers: CLDK378AUS23