Inclusion Criteria:
1. Patients ≥ 18 years of age.
2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Adequate organ function as follows (specimens must be collected during the Screening
Period within 7 days prior to entering the Treatment Period):
1. ANC ≥ 1000/μL. 2. Hemoglobin > 9 g/dL. 3. Platelet count > 75,000/μL. 4. Calculated creatinine clearance ≥ 60 mL/min (using the Cockcroft-Gault formula or
using other formulae per institutional guidelines)
5. Serum total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN for patients with
total bilirubin levels > 1.5 × ULN. Known Gilbert syndrome is allowed if total
bilirubin is <3 × ULN. 6. AST and ALT ≤ 2.5 × ULN (or ≤ 5 × ULN if liver function abnormalities are due to
underlying liver metastases)
7. Coagulation: ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy, as
long as prothrombin time, international normalized ratio, or activated partial
thromboplastin time is within therapeutic range of intended use of anticoagulants
when applicable. 4. Left ventricular ejection fraction ≥ 50% by echocardiogram or radionuclide test.
5. Patients must have recovered from the side effects of prior cancer-specific therapy to
a minimum of ≥ Grade 1 by NCI-CTCAE version 5.0 criteria or return to baseline.
Exceptionally, patients with ≤ Grade 2 neuropathy or other TRAEs may be eligible after
discussion with the Sponsor.
6. Washout period since receipt of the last dose of prior anticancer therapy (including
other investigational therapy):
1. Checkpoint inhibitors such as cytotoxic T-lymphocyte-associated protein 4
(CTLA-4), programmed cell death protein 1 (PD-1), or programmed death ligand 1
(PD-L1) inhibitors: ≥ 4 weeks. 2. For all other biologic agents (e.g., antiangiogenics): ≥ 3 weeks or a minimum of
their dosing interval if shorter than 3 weeks (e.g., agents administered every 2
weeks would require a 2-week washout period)
3. All other investigational agents: ≥ 4 weeks or ≥ 5 × t1/2, whichever is shorter.
7. If feasible, patients must be willing to consent to the submission of formalin-fixed
paraffin-embedded (FFPE) tissue blocks of tumor tissue, preferably from a
pretreatment, fresh tumor biopsy. Alternatively, archival tumor FFPE blocks or, ≥ 20
unstained slides of tumor tissue from available archival sources that are < 2 years
old are acceptable.
8. Highly effective contraception for both male and female patients from Screening
through 5 months after the last dose of study drug if the possibility of conception
exists.
9. Patient or their legally acceptable representative must be able and willing to:
1. Provide Institutional Review Board-or Institutional Ethics Committee-approved
written informed consent in accordance with regulatory and institutional
guidelines. This must be obtained before the performance of any protocol-related
procedures that are not part of normal patient care.
2. Comply with the study protocol and with the planned biopsy procedures.
Inclusion Criteria for Dose Escalation Patients. 10. Patients must have histologically or cytologically confirmed solid tumor malignancies
that are advanced and unresectable, or metastatic with no available therapy known to
confer clinical benefit, as evaluated by the treating physician. There is no upper
limit on the number of prior lines of anticancer therapy received. Tumors must have
confirmed RAS/RAF gene alterations as determined by next-generation sequencing or
fluorescence in situ hybridization, as documented by local testing:
1. NRASmut solid tumors, including but not limited to melanoma, CRC, and others. 2. KRASmut solid tumors, including but not limited to NSCLC, pancreatic carcinoma,
and CRC. 3. BRAFmut Class I/II/ III or BRAF fusions solid tumors, including but not limited
to melanoma, NSCLC, thyroid carcinoma. 4. CRAF-altered solid tumors (mutations and gene fusions)
5. NF1mut solid tumors, including but not limited to nerve sheath tumors, gliomas,
malignant melanoma, breast cancer, and others. 11. Patients who have measurable or evaluable disease by RECIST 1.1 criteria, as assessed
by the Investigator/local radiologist.
Inclusion Criteria for Dose Expansion Patients. 12. All patients must have a histological diagnosis of an advanced, unresectable, locally
recurrent, or metastatic disease with no available therapy known to confer clinical
benefit, as evaluated by the treating physician. There is no upper limit on the number
of prior lines of anticancer therapy received.
13. Patients must be enrolled in 1 of the following 4 dose expansion cohorts:
1. Cohort 1: Molecularly confirmed NRASmut CRC as determined by local test results. 2. Cohort 2: Molecularly confirmed NRASmut malignant melanoma as determined by local
test results. 3. Cohort 3 Molecularly confirmed KRASmut NSCLC as determined by local test results. 4. Cohort 4: Any solid tumors with molecularly confirmed pathogenic BRAF non-V600X
mutations or fusions, or pathogenic CRAF mutations or fusions as determined by
local test results. 14. Patients must have ≥ 1 measurable lesion per RECIST 1.1 criteria as assessed by the
Investigator/local radiologist. Lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesions.
Exceptionally, patients with tumors that are evaluable but non-measurable per RECIST
1.1 criteria can be enrolled following approval by the Sponsor.
Exclusion Criteria:
1. Patients with any active central nervous system (CNS) lesion either symptomatic or
radiologically unstable and/or leptomeningeal metastasis. However, patients previously
treated for these conditions that have had stable CNS disease (verified with
consecutive imaging studies) for > 3 months, are asymptomatic and are not currently
taking corticosteroids, or are on stable dose or decreasing of corticosteroids for ≥ 7
days prior to enrollment are eligible.
2. Patients who have not recovered to ≤ Grade 1 or baseline from all AEs due to prior
anticancer therapies. Exceptionally, patients with ≤ Grade 2 neuropathy or other TRAEs
may be eligible after discussion with the Sponsor.
3. Any other concurrent antineoplastic treatment or investigational agent except for
localized radiation therapy for symptom palliation (to be considered nontarget lesions
after treatment) and/or hormonal therapy for ductal DCIS/LCIS/Stage 1 breast cancer
that has been stable on therapy for ≥ 3 years.
4. Uncontrolled or life-threatening symptomatic concomitant disease (including known
symptomatic HIV-positive with an active AIDS-defining opportunistic infection or a
current CD4 count < 350 cells/μL; symptomatic active hepatitis B or C checked at
screening; or active tuberculosis). Patients with HIV are eligible if:
1. They have received antiretroviral therapy (ART) as clinically indicated for ≥ 4
weeks prior to entering the Treatment Period of the study;
2. They continue on ART as clinically indicated while on study;
3. CD4 counts and viral loads are monitored per standard of care by a local health
care provider.
5. Has received prior radiotherapy for palliation ≤ 2 weeks prior to the first dose of
study treatment. Patients must have recovered from all radiation-related toxicities.
6. History of a second malignancy requiring systemic treatment ≤ 3 years prior to
enrollment. Patients who have remained cancer-free ≤ 3 years of enrollment are
eligible. Patients with history of prior early stage basal/squamous cell skin cancer
or noninvasive or in situ cancers that have undergone definitive treatment at any
prior time are eligible.
7. Clinically significant cardiovascular disease:
1. Cerebral vascular accident/stroke (< 6 months prior to enrollment)
2. Myocardial infarction (< 6 months prior to enrollment)
3. Unstable angina (< 6 months prior to enrollment)
4. Congestive heart failure (New York Heart Association Classification Class III or
IV)
5. The presence of any condition that can increase proarrhythmic risk (e.g.,
hypokalemia, bradycardia, heart block), including any new, unstable, or serious
cardiac arrhythmia requiring medication, or other baseline arrhythmias that might
interfere with interpretation of ECGs on study (e.g., bundle branch block).
6. Patients with QT interval corrected by Fridericia's formula (QTcF) > 470 msec for
both men and women on screening ECG are excluded. Patients with a bundle branch
block must have QT interval corrected for bundle branch block.
7. Patients who are on stable doses of concomitant medication with known
prolongation of QTcF if QTcF is > 470 msec.
8. Known previous or current serious ophthalmic disorders, including history of glaucoma,
history of retinal vein occlusion (RVO) or current risk factors for RVO, history of
retinal pathology or evidence of retinal pathology.
9. Active skin disorder requiring systemic treatment ≤3 months prior to start of study
treatment.
10. History of rhabdomyolysis ≤3 months prior to start of study treatment.
11. Patients taking any medication on the prohibited medication list are excluded from the
study unless they can be transferred to other medications.
12. Has an active infection requiring systemic therapy.
13. A woman of childbearing potential who has a positive pregnancy test prior to
initiating study treatment.
14. Breastfeeding or expecting to conceive or father children within the projected
duration of the study, starting with the Screening visit through 5 months after the
last dose of study treatment.
15. Patients who are unable to swallow or retain oral medication.
