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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01877811
Recruitment Status : Completed
First Posted : June 14, 2013
Last Update Posted : April 25, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE May 6, 2013
First Posted Date  ICMJE June 14, 2013
Last Update Posted Date April 25, 2019
Study Start Date  ICMJE June 2013
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 13, 2016)
  • Phase 1: Dose Limiting Toxicities [ Time Frame: Approximately 12 months ]
    From signing of the informed consent up to approximately 12 months
  • Phase 1: Occurrence of Adverse Events [ Time Frame: Approximately 12 months ]
    From signing of the informed consent up to approximately 12 months
  • Phase 1b: Occurrence of Adverse Events [ Time Frame: Approximately 12 months ]
    To further assess the safety profile and tolerability of RXDX-105 at the RP2D
Original Primary Outcome Measures  ICMJE
 (submitted: June 11, 2013)
Objective Response Rate [ Time Frame: Approximately 12 months ]
The primary efficacy variable is the objective response rate calculated as the number of responders (i.e., CR or PR) in each patient group divided by the number of evaluable patients in that patient group.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 13, 2016)
  • Phase 1: Maximum observed plasma drug concentration (Cmax) [ Time Frame: Day 1 to Day 16 ]
  • Phase 1: Time of maximum observed plasma drug concentration (tmax) [ Time Frame: Day 1 to Day 16 ]
  • Phase 1: Area under the plasma drug concentration versus time curve from time 0 to infinity (AUC0-∞) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Day 1 to Day 16 ]
  • Phase 1: Terminal elimination rate constant (λz) [ Time Frame: Day 1 to Day 16 ]
  • Phase 1: Terminal elimination half-life (t1/2) [ Time Frame: Day 1 to Day 16 ]
  • Phase 1: Apparent clearance of study drug from plasma (CL/F) [ Time Frame: Day 1 to Day 16 ]
  • Phase 1b: Objective Response Rate [ Time Frame: Approximately 12 months ]
    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
  • Phase 1b: Duration of Objective Response [ Time Frame: Approximately 12 months ]
    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
  • Phase 1b: Clinical Benefit Rate [ Time Frame: Approximately 12 months ]
    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
Original Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2013)
  • Duration of Objective Response [ Time Frame: Approximately 12 months ]
    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
  • Disease Control Rate [ Time Frame: Approximately 12 months ]
    The disease control rate is defined as the proportion of patients achieving best overall response of CR, PR, or stable disease (SD), as assessed using RECIST v1.1
  • Progression-free Survival [ Time Frame: Approximately 12 months ]
    Progression-free survival is defined as the time interval from date of first dose of study drug to first documented disease progression or death from any cause, whichever occurs first
  • Overall Survival [ Time Frame: Approximately 12 months ]
    Overall survival is defined as the time interval from date of first dose of study drug to date of death from any cause.
  • Maximum observed plasma drug concentration (Cmax) [ Time Frame: Day 1 to Day 16 ]
  • Time of maximum observed plasma drug concentration (tmax) [ Time Frame: Day 1 to Day 16 ]
  • Area under the plasma drug concentration versus time curve from time 0 to infinity (AUC0-∞) [ Time Frame: Day 1 to Day 16 ]
  • Area under the plasma drug concentration versus time curve from time 0 to the last measureable drug concentration (AUC0-t) [ Time Frame: Day 1 to Day 16 ]
  • Area under the plasma drug concentration versus time curve from time 0 to 24 hours [ Time Frame: Day 1 to Day 16 ]
  • Terminal elimination rate constant (λz) [ Time Frame: Day 1 to Day 16 ]
  • Terminal elimination half-life (t1/2) [ Time Frame: Day 1 to Day 16 ]
  • Apparent clearance of study drug from plasma (CL/F) [ Time Frame: Day 1 to Day 16 ]
  • Apparent volume of distribution (V/F) [ Time Frame: Day 1 to Day 16 ]
  • Percentage extrapolation [ Time Frame: Day 1 to Day 16 ]
  • Predicted accumulation ratio [ Time Frame: Day 1 to Day 16 ]
  • AUC for 1 dosing interval following multiple doses only (AUCτ) [ Time Frame: Day 1 to Day 15 ]
  • AUC0-t [ Time Frame: Day 1 to Day 15 ]
  • Cmax [ Time Frame: Day 1 to Day 15 ]
  • Tmax [ Time Frame: Day 1 to Day 15 ]
  • Observed accumulation ratio (Robs) [ Time Frame: Day 1 to Day 15 ]
  • Steady-state accumulation ratio (Rss) [ Time Frame: Day 1 to Day 15 ]
  • Dose Limiting Toxicities [ Time Frame: From signing of the informed consent up to approximately 12 months. ]
  • Occurrence of Adverse Events [ Time Frame: From signing of the informed consent up to approximately 12 months. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of RXDX-105, Potent RET Inhibitor in Patients With Advanced Lung Cancer and Other Solid Tumors
Official Title  ICMJE An Open-Label, Phase 1/1b, Single-Agent Study of RXDX-105 in Patients With Advanced Solid Tumors
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumors
Intervention  ICMJE 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 Name: CEP-32496, AC013773
Study Arms  ICMJE Experimental: RXDX-105
Intervention: Drug: RXDX-105
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 2, 2017)
143
Original Estimated Enrollment  ICMJE
 (submitted: June 11, 2013)
154
Actual Study Completion Date  ICMJE February 2019
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Australia,   New Zealand,   Russian Federation
 
Administrative Information
NCT Number  ICMJE NCT01877811
Other Study ID Numbers  ICMJE RXDX-105-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Hoffmann-La Roche
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP