Clinical trial NCT01877811: Study of RXDX-105, Potent RET Inhibitor in Patients With Advanced Lung Cancer and Other Solid Tumors
Official title: An Open-Label, Phase 1/1b, Single-Agent Study of RXDX-105 in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: Lung Cancer
RET Inhibitor
Solid Tumors
RET mutations or rearrangements
BRAF mutations or rearrangements
Squamous NSCLC
KRAS mutation
Other Lung adenocarcinomas
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-06-14
Enrollment: 143
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase 1: Dose Limiting Toxicities
timeFrame: Approximately 12 months
measure: Phase 1: Occurrence of Adverse Events
timeFrame: Approximately 12 months
measure: Phase 1b: Occurrence of Adverse Events
timeFrame: Approximately 12 months
Secondary outcomes:
measure: Phase 1: Maximum observed plasma drug concentration (Cmax)
timeFrame: Day 1 to Day 16
measure: Phase 1: Time of maximum observed plasma drug concentration (tmax)
timeFrame: Day 1 to Day 16
measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to infinity (AUC0-∞)
timeFrame: Day 1 to Day 16
measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to the last measureable drug concentration (AUC0-t)
timeFrame: Day 1 to Day 16
measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to 24 hours after study drug administration (AUC0-24)
timeFrame: Day 1 to Day 16
measure: Phase 1: Terminal elimination rate constant (λz)
timeFrame: Day 1 to Day 16
measure: Phase 1: Terminal elimination half-life (t1/2)
timeFrame: Day 1 to Day 16
measure: Phase 1: Apparent clearance of study drug from plasma (CL/F)
timeFrame: Day 1 to Day 16
measure: Phase 1b: Objective Response Rate
timeFrame: Approximately 12 months
measure: Phase 1b: Duration of Objective Response
timeFrame: Approximately 12 months
measure: Phase 1b: Clinical Benefit Rate
timeFrame: Approximately 12 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Irvine
country: United States
facility: University of California Irvine College of Medicine
state: California
city: San Diego
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Washington
country: United States
facility: Lombardi Comprehensive Cancer Center, Georgetown
state: District of Columbia
city: Sarasota
country: United States
facility: Florida Cancer Center
state: Florida
city: Athens
country: United States
facility: University Cancer & Blood Center, LLC
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital/Beth Israel Deaconess Med. Ctr./Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: University of Washington, Seattle Cancer Care Alliance
state: Washington
Study officials:
References:
citation: 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.