Study of RXDX-105, Potent RET Inhibitor in Patients With Advanced Lung Cancer and Other Solid Tumors

An Open-Label, Phase 1/1b, Single-Agent Study of RXDX-105 in Patients With Advanced Solid Tumors

This is a first-in-human, multicenter, open-label study consisting of 2 phases. Phase 1 is a dose escalation study of RXDX-105 (formerly known as CEP-32496) in patients with advanced solid tumors aimed at defining the recommended Phase 2 dose (RP2D) and schedule for administration. Phase 1b is a dose expansion in approximately 90 patients with advanced solid tumors with specific histologies and/or molecular alterations of interest. Patients in Phase 1b will be treated at the RP2D determined in Phase 1.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: RXDX-105

Detailed Description

The primary objective of Phase 1 is to determine the recommended Phase 2 dose (RP2D) of RXDX-105. The primary objective of Phase 1b is to further assess the safety profile and tolerability of RXDX-105 at the RP2D The secondary objective is to evaluate the antitumor activity of RXDX-105 at the RP2D, as assessed by objective response rate (ORR) (complete response [CR] or partial response [PR]) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) in patients with advanced solid tumors with RET or BRAF mutations or rearrangements.

The RP2D has been determined and Phase 1 portion of the study is now closed to new patient enrollment.

Phase 1 b is open and enrolling patients with solid tumors harboring a RET rearrangement or mutation, or a BRAF rearrangement or mutation. Additionally, patients with Squamous NSCLC and lung adenocarcinomas with other alterations than RET or BRAF such as KRAS mutations, etc. will also be enrolled. Approximately 90 patients will be enrolled in Phase 1b.

Each phase of this study will consist of a 28-day screening period. Patients will be treated in 28-day treatment cycles until documented radiographic progression, unacceptable toxicity, withdrawal of consent, or protocol specified parameters to stop treatment. Patients in Phase 1 and 1b will be followed for 6 months after the last dose of study treatment.

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States
      • City of Hope
    • Irvine, California, United States
      • University of California Irvine College of Medicine
    • San Diego, California, United States
      • University of California San Diego Moores Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States
      • Lombardi Comprehensive Cancer Center, Georgetown
  • Florida
    • Sarasota, Florida, United States
      • Florida Cancer Center
  • Georgia
    • Athens, Georgia, United States
      • University Cancer & Blood Center, LLC
  • Massachusetts
    • Boston, Massachusetts, United States
      • Massachusetts General Hospital/Beth Israel Deaconess Med. Ctr./Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States
      • Henry Ford Health System
    • Detroit, Michigan, United States
      • Karmanos Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington University
  • New York
    • New York, New York, United States
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Fox Chase Cancer Center
  • Texas
    • Houston, Texas, United States
      • University of Texas MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States
      • University of Washington, Seattle Cancer Care Alliance

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 for Phase 1b:

1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory

   • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available

2. Prior Treatment:

   • Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed
   • NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve
   • Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies
3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease
4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. The use of seizure prophylaxis is allowed. Patients requiring steroids must be at a stable or decreasing dose for at least 2 weeks prior to the start of RXDX-105 treatment.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
6. Able to ingest oral medication
7. Other inclusion criteria apply

Exclusion Criteria for Phase 1b:

1. Treated with systemic anticancer therapy or an investigational agent within 2 weeks or 5 half-lives, whichever is shorter, prior to start of study drug treatment (4 weeks for antibody therapy and immunotherapy, and 2 weeks for bevacizumab in colon cancer patients)
2. Major surgery 21 days or less prior to starting study drug or has not recovered from adverse effects of such therapy
3. Radiotherapy within 2 weeks prior to start of study drug treatment (palliative radiation or stereotactic radiosurgery within 7 days prior to start of study treatment). Patients must have recovered from all radiotherapy-related toxicities
4. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 500 milliseconds from ECGs performed at least 24 hours apart)
5. Major active infection requiring parenteral antibiotics
6. Severe or unstable medical condition, such as congestive heart failure (New York Heart Association [NYHA] Class III or IV), ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric condition, as well as an uncontrolled cardiac arrhythmia requiring medication (≥ Grade 2, according to NCI CTCAE v4.03), myocardial infarction within 6 months prior to starting study treatment, or any other significant or unstable concurrent medical illness that in the opinion of the Investigator would preclude protocol therapy
7. History of other previous cancer that would interfere with the determination of safety or efficacy of RXDX-105 with respect to the qualifying solid tumor malignancy
8. Known infection with human immunodeficiency virus (HIV) and active hepatitis B or hepatitis C
9. Current participation in another clinical study of an investigational agent, vaccine, or device. Concomitant participation in observational studies is acceptable
10. Presence of a significant gastrointestinal disorder that, in the opinion of the Investigator or Sponsor, could interfere with absorption of RXDX-105 (e.g., malabsorption syndrome, gastrointestinal surgery)
11. Known hypersensitivity to any of the components of RXDX-105

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: RXDX-105

Drug: RXDX-105; During Phase 1/1b, subjects will receive daily oral doses of RXDX-105 in 28-day cycles (except for Day 2 of Cycle 1). To determine the recommended Phase 2 dose (RP2D), doses will be administered in an escalated fashion starting at 20 mg/day. During Phase 1b, subjects will be administered the RP2D in 28-day treatment cycles until documented radiographic progression, unacceptable toxicity, withdrawal of consent, or protocol specified parameters to stop treatment.; Other Names: CEP-32496, AC013773

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Dose Limiting Toxicities	From signing of the informed consent up to approximately 12 months	Approximately 12 months
Phase 1: Occurrence of Adverse Events	From signing of the informed consent up to approximately 12 months	Approximately 12 months
Phase 1b: Occurrence of Adverse Events	To further assess the safety profile and tolerability of RXDX-105 at the RP2D	Approximately 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Maximum observed plasma drug concentration (Cmax)		Day 1 to Day 16
Phase 1: Time of maximum observed plasma drug concentration (tmax)		Day 1 to Day 16
Phase 1: Area under the plasma drug concentration versus time curve from time 0 to infinity (AUC0-∞)		Day 1 to Day 16
Phase 1: Area under the plasma drug concentration versus time curve from time 0 to the last measureable drug concentration (AUC0-t)		Day 1 to Day 16
Phase 1: Area under the plasma drug concentration versus time curve from time 0 to 24 hours after study drug administration (AUC0-24)		Day 1 to Day 16
Phase 1: Terminal elimination rate constant (λz)		Day 1 to Day 16
Phase 1: Terminal elimination half-life (t1/2)		Day 1 to Day 16
Phase 1: Apparent clearance of study drug from plasma (CL/F)		Day 1 to Day 16
Phase 1b: Objective Response Rate	Objective response rate is defined as the proportion of patients with advanced solid tumors achieving best overall response of complete response (CR), or partial response (PR), as assessed using RECIST v1.1	Approximately 12 months
Phase 1b: Duration of Objective Response	The duration of objective response is defined as the time interval from the date of first documented response (CR or PR) to disease progression or death, whichever occurs first	Approximately 12 months
Phase 1b: Clinical Benefit Rate	Clinical benefit rate is defined as the proportion of patients achieving a complete response (CR), partial response (PR) or stable disease (SD) for 6 months	Approximately 12 months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Morano F, Fuca G, Nikolinakos P, Drilon A, Hechtman JF, Christiansen J, Gowen K, Frampton GM, Gasparini P, Rossini D, Gigliotti C, Kim ST, Prisciandaro M, Hodgson J, Zaniboni A, Chiu VK, Milione M, Patel R, Miller V, Bardelli A, Novara L, Wang L, Pupa SM, Sozzi G, Ross J, Di Bartolomeo M, Bertotti A, Ali S, Trusolino L, Falcone A, de Braud F, Cremolini C. RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. Ann Oncol. 2018 Jun 1;29(6):1394-1401. doi: 10.1093/annonc/mdy090.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): February 1, 2019

Study Registration Dates

• First Submitted: May 6, 2013
• First Submitted That Met QC Criteria: June 11, 2013
• First Posted (Estimate): June 14, 2013

Study Record Updates

• Last Update Posted (Actual): April 25, 2019
• Last Update Submitted That Met QC Criteria: April 24, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Lung Cancer; Squamous NSCLC; KRAS mutation; Solid Tumors; RET Inhibitor; RET mutations or rearrangements; BRAF mutations or rearrangements; Other Lung adenocarcinomas
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Agerafenib
• Other Study ID Numbers: RXDX-105-01