| Eligibility |
Inclusion Criteria The following criteria must be met by ALL subjects
1. Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 (Phase 1) or immune-related (ir)RECIST 1.1 (Phase 1b and Roll-over Cohort). Tumor
lesions situated in a previously irradiated area are considered measurable if
progression has been demonstrated in such lesions
2. Minimum estimated life expectancy of 3 months
3. Age 18 years or older
4. Must have adequate organ function, including the following:
- Absolute neutrophil count (ANC) = 1.5 x109/L; platelet count = 100 x 109/L;
hemoglobin = 9 g/dL or = 5.6 mmol/L
- International normalized ratio (INR) or prothrombin time (PT) and activated
partial thromboplastin Time (aPTT) = 1.5 times the upper limit of normal (ULN)
unless subject is receiving anticoagulant therapy as long as PT or aPTT is within
therapeutic range of intended use of anticoagulants
- Hepatic: total bilirubin = 1.5 times ULN, aspartate transaminase (AST) and/or
alanine aminotransferase (ALT) = 2.5 times ULN (= 5 times ULN if liver
metastases)
- Renal: serum creatinine = 1.25 times the ULN or estimated creatinine clearance =
60 mL/min (Cockcroft and Gault formula
[http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/])
5. Recovery (to baseline or to Grade 1 or less) from prior treatment-related toxicities
6. Ability to swallow capsules
7. Ability to comply with treatment, laboratory monitoring and required clinic visits
8. Able to understand and willing to sign the informed consent form (ICF)
In addition, the following criteria must be met based on the group to be enrolled into:
For subjects in the Phase 1 Single Agent CGX1321 Dose Escalation phase:
1. Pathologically-confirmed, locally advanced or metastatic solid tumors in subjects that
have relapsed or are refractory to or are not considered medically suitable to receive
standard of care treatment
2. Eastern Cooperative Oncology Group (ECOG) score of 0 - 2
3. Willingness for subjects of reproductive potential to use adequate methods of
contraception during and for 3 months after study treatment
For subjects in the Phase 1 Single Agent CGX1321 Dose Expansion phase:
1. Histologically diagnosed advanced GI tumors, such as colorectal adenocarcinoma,
gastric adenocarcinoma, pancreatic adenocarcinoma, bile duct carcinoma, hepatocellular
carcinoma, esophageal carcinoma in subjects that have relapsed or are refractory to or
are not considered medically suitable to receive standard of care treatment. Subjects
must have confirmed genetic alterations (e.g., Rspo2 fusion, Rspo3 fusion or predicted
loss-of-function mutations in RNF43) upstream in the WNT pathway and no predicted
change-of-function alterations in genes (e.g., APC, CTNNB1 and Axin1) downstream in
the WNT pathway
2. ECOG score of 0 - 2
3. Willingness for subjects of reproductive potential to use adequate methods of
contraception during and for 3 months after study treatment
For subjects in the Phase 1b or Roll-over Cohort CGX1321 in combination with pembrolizumab:
1. Histologically or cytologically confirmed diagnosed advanced colorectal tumors that
are mismatch repair-proficient or MSS in subjects that have relapsed or are refractory
to or are not considered medically suitable to receive standard of care treatment (for
dose escalation) and histologically or cytologically confirmed diagnosed advanced
colorectal tumors with confirmed genetic alterations (e.g., Rspo2 fusion, Rspo3 fusion
or predicted loss-of-function mutations in RNF43) upstream in the WNT pathway and no
predicted change-of-function alterations in genes (e.g., APC, CTNNB1 and Axin1)
downstream in the WNT pathway (for dose expansion) Note: Not applicable for subjects
entering Roll-over Cohort
2. Previous enrollment into either Phase 1 single agent dose escalation or Phase 1 single
agent dose expansion with documented disease progression while on treatment with
single agent CGX1321 Note: Not applicable for subjects entering Phase 1b
3. ECOG score of 0 - 1
4. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of pembrolizumab. Subjects of
childbearing potential are those who have not been surgically sterilized or have been
free from menses for > 1 year.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject Female subjects of childbearing potential must have a negative serum
pregnancy test within 72 hours prior to receiving the first dose of study treatment Male
subjects of childbearing potential must agree to use an adequate method of contraception
starting with the first dose of pembrolizumab through 120 days after the last dose of
pembrolizumab Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject
For subjects in the Phase 1b Cohort CGX1321 in Combination with Encorafenib + Cetuximab:
1. Histologically diagnosed advanced colorectal tumors (CRC) carrying a BRAF V600E
mutation in tumor tissue, (as detected by an FDA-approved test) with confirmed genetic
alterations (e.g., Rspo2 fusion, Rspo3 fusion or predicted loss-of-function mutations
in RNF43) upstream in the WNT pathway and no predicted change-of-function alterations
in genes (e.g., APC, CTNNB1 and Axin) downstream in the WNT pathway
2. Have relapsed or are refractory to or are not considered medically suitable to receive
standard of care treatment in the metastatic setting Note: Prior treatment with
encorafenib + cetuximab is will be is permitted Exclusion Criteria
All subjects must be excluded from participating in the study if subjects meet any of the
following criteria:
1. Prior exposure to a WNT inhibitor. Note: Not applicable for subjects entering
Roll-over Cohort
2. Received any of the following within the specified time frame prior to administration
of study drug:
• Previous therapy for malignancy within 21 days, including any investigational
agents, chemotherapy, immunotherapy, biological or hormonal therapy Note: Only
applicable for subjects in single-agent dose escalation cohorts
3. Major surgery within 4 weeks of first dose of study treatment
4. Radiotherapy within 2 weeks of first dose of study treatment. Note for Phase 1b or
Roll-over Cohorts: Subjects must have recovered from all radiation-related toxicities,
not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout
is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease.
5. Significant GI or variceal bleeding or subdural hematoma within 3 months of first dose
of study treatment
6. Known active central nervous system metastases and/or carcinomatous meningitis Note:
Subjects with previously treated brain metastases may participate provided they are
radiographically stable (without evidence of progression by imaging (using the
identical imaging modality for each assessment, either magnetic resonance imaging
[MRI] or computed tomography [CT] scan) for at least four weeks prior to the first
dose of study treatment and any neurologic symptoms have returned to baseline), have
no evidence of new or enlarging brain metastases, and are not using steroids for at
least 14 days prior to the first dose of study treatment. This exception does not
include carcinomatous meningitis which is excluded regardless of clinical stability
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug
8. Currently receiving medications known to be inhibitors of CYP3A4/5. Subjects currently
receiving medications of known inducers of CYP3A4/5 or substrates of CYP2C8/9 and
CYP1A2 may be excluded unless determined by the Investigator to be in the best
interest of the subject and are approved by the Sponsor
9. Osteoporosis based on a T-score of < -2.5 at the left or right total hip, left or
right femoral neck or lumbar spine (L1 - L4) as determined by dual-energy x-ray
absorptiometry (DXA) scan
10. Subjects with bone metastases that:
- Have a prior history of a pathologic fracture
- Have a lytic lesion requiring an orthopedic intervention or
- Are not receiving a bisphosphonate (zoledronic acid or denosumab) as per
institutional guidelines
11. Current bisphosphonate therapy for symptomatic hypercalcemia
12. History within last 6 months of New York Heart Association Class III or IV heart
failure, acute myocardial infarction, angina pectoris, uncontrolled arrhythmia, acute
coronary syndromes, stent placement, uncontrolled hypertension
13. Subjects with QTc interval of > 470 msec
14. Known human immunodeficiency virus positive (such patients are at increased risk of
lethal infections when treated with potentially marrow-suppressive therapy)
15. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer
16. Active systemic infection requiring IV antibiotics within 2 weeks of the first dose of
study treatment
17. History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the study, interfere with the subject's participation
for the full duration of the study, or is not in the best interest of the subject to
participate, in the opinion of the treating Investigator
18. Known psychiatric or substance abuse disorders that would interfere with the subject's
ability to cooperate with the requirements of the study.
19. Pregnancy or lactation
20. Has had an allogeneic tissue/solid organ transplant
In addition, subjects must be excluded from participating if they meet any of the following
criteria based on the group to be enrolled into:
For subjects in the Phase 1 Single Agent CGX1321 Dose Escalation or Dose Expansion phase:
1. Known active hepatitis A, B or C Note: Subjects who are HBsAg+ and have DNA load < 2000
IU/mL (104 copies/mL) are eligible to participate in the Phase 1 study
For subjects in the Phase 1b or Roll-over Cohort CGX1321 in combination with pembrolizumab:
1. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local
health authority
2. Received transfusion of blood products (including platelets or red blood cells) or
administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant
erythropoietin) within 4 weeks prior to first dose of study treatment
3. Active autoimmune disease that has required systemic treatment in past 2 years (i.e.,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment
4. History of (non-infectious) pneumonitis that required steroids or current pneumonitis
5. History of interstitial lung disease
6. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of study treatment
7. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4,
OX 40, CG137) and was discontinued from that treatment due to a Grade 3 or higher irAE
or if the patient has previously participated in Merck MK-3475 clinical studies
8. Has severe (= Grade 3) hypersensitivity to any of the excipients of pembrolizumab
9. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Day 1 or
who has not recovered (i.e., = Grade 1 or at baseline) from AEs due to agents
administered more than 4 weeks earlier
10. Received a live-virus vaccination within 30 days of planned treatment start. Seasonal
flu vaccines that do not contain live virus are permitted
For subjects in the Phase 1b Cohort CGX1321 in Combination with Encorafenib + Cetuximab:
1. Symptomatic brain metastases or leptomeningeal disease
2. History or current evidence of retinal vein occlusion or current risk factors for
retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of
hyperviscosity or hypercoagulability syndromes)
3. Known history of acute or chronic pancreatitis
4. History of chronic inflammatory bowel disease or Crohn's disease requiring medical
intervention (immunomodulatory or immunosuppressive medications or surgery) =12 months
prior to enrollment
5. Uncontrolled blood pressure despite medical treatment
6. Impaired GI function or disease that may significantly alter the absorption of
encorafenib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome,
small bowel resection with decreased intestinal absorption)
7. History of thromboembolic or cerebrovascular events = 6 months prior to starting study
treatment including transient ischemic attacks, cerebrovascular accidents, deep vein
thrombosis or pulmonary emboli
8. Concurrent neuromuscular disorder that is associated with the potential of elevated
creatinine (phosphor)kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy,
amyotrophic lateral sclerosis, spinal muscular atrophy)
9. Active hepatitis B or hepatitis C infection
10. Known history of Gilbert's syndrome
11. Known contraindication to receive Encorafenib or Cetuximab at the planned doses
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