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.
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.
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
