Clinical Trial Finder

Comments

CGX1321: a Wnt inhibitor, oral.
pembrolizumab: immunotherapy, anti PD-1 checkpoint inhibitor, Keytruda.
The wnt pathway is inversely correlated with T cell infiltration, hence the rationale of inhibiting it while administering CI.

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Inclusion Criteria

Inclusion Criteria The following criteria must be met by ALL subjects

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
Minimum estimated life expectancy of 3 months
Age 18 years or older

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/])
Recovery (to baseline or to Grade 1 or less) from prior treatment-related toxicities
Ability to swallow capsules
Ability to comply with treatment, laboratory monitoring and required clinic visits
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:

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
Eastern Cooperative Oncology Group (ECOG) score of 0 - 2
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:

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
ECOG score of 0 - 2
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:

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
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
ECOG score of 0 - 1
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:

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
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

Exclusion Criteria

All subjects must be excluded from participating in the study if subjects meet any of the following criteria:

Prior exposure to a WNT inhibitor. Note: Not applicable for subjects entering Roll-over Cohort

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

Major surgery within 4 weeks of first dose of study treatment
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.
Significant GI or variceal bleeding or subdural hematoma within 3 months of first dose of study treatment
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
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
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
Osteoporosis based on a T-score of 470 msec
Known human immunodeficiency virus positive (such patients are at increased risk of lethal infections when treated with potentially marrow-suppressive therapy)
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
Active systemic infection requiring IV antibiotics within 2 weeks of the first dose of study treatment
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
Known psychiatric or substance abuse disorders that would interfere with the subject's ability to cooperate with the requirements of the study.
Pregnancy or lactation
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:

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

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
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
History of (non-infectious) pneumonitis that required steroids or current pneumonitis
History of interstitial lung disease
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
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
Has severe (≥ Grade 3) hypersensitivity to any of the excipients of pembrolizumab
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
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:

Symptomatic brain metastases or leptomeningeal disease
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)
Known history of acute or chronic pancreatitis
History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to enrollment
Uncontrolled blood pressure despite medical treatment
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)
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
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)
Active hepatitis B or hepatitis C infection
Known history of Gilbert's syndrome
Known contraindication to receive Encorafenib or Cetuximab at the planned doses