Clinical Trials

Inclusion Criteria:

• Written informed consent, according to local guidelines, signed and dated by the participant prior to the performance of any study-specific procedures, sampling, or analyses.
• Participant must be ≥ 18 years of age at the time of signature of the informed consent form (ICF).
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Has histologically or cytologically confirmed cancer that meets the following criteria:
  • Dose Escalation Phase
    • Has metastatic disease, or locally advanced disease that is not a candidate for curative surgery or curative radiation.
    • Cohort A0 (JAB-3312 + pembrolizumab):
      • Advanced solid tumors that typically are responsive to anti-PD1/PD-L1 monotherapy (based on prior clinical studies of this class of agents).
      • Naïve to SHP2 inhibitors.
    • Cohort B0 (JAB-3312 + binimetinib):
      • Has any cancer type, with known mutations in KRAS G12.
      • Naïve to MEK, SHP2 or ERK inhibitors.
      • Received at least 1 and no more than 2 previous lines of systemic therapy. Must either demonstrate progression or become intolerant to the previous line of therapy.
  • Dose Expansion Phase
    • Cohorts A1, A2, A3 (JAB-3312 + pembrolizumab):
      • Naïve to anti-PD-1/PD-L1 agents and SHP2 inhibitors.
      • Have provided a formalin fixed tumor tissue sample (collected within ≤18 months) from a biopsy of a tumor lesion either at the time of or after the diagnosis of metastatic disease has been done.
    • Cohort A1 (NSCLC):
      • Patients with metastatic or locally advanced NSCLC who are not candidates for curative surgery or curative radiation.
      • Do not have an EGFR mutation, ALK translocation, or other actionable molecular alterations that can be treated with Food and Drug Administration (FDA) approved targeted agents.
      • PD-L1 tumors expression of 1% or greater (TPS ≥1%) as determined by a local institutional standard.
      • Received no prior systemic treatment for advanced disease.
    • Cohort A2 (HNSCC):
      • Histologically or cytologically confirmed diagnosis of metastatic or locally advanced HNSCC that is considered not amenable to further therapy with curative intent.
      • Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx are allowed.
      • Tumors expressing PD-L1 (CPS ≥1) as determined by a local institutional standard.
      • Received no prior systemic treatment for advanced disease.
    • Cohort A3 (ESCC):
      • Histologically or cytologically confirmed diagnosis of metastatic or locally advanced ESCC that is not amenable for curative intervention.
      • Tumors expressing PD-L1 (CPS ≥10) as determined by a local institutional standard.
      • Received only 1 previous line of standard systemic therapy for advanced disease. Must either demonstrate progression or become intolerant to the previous line of therapy.
    • Cohort B1, B2 (JAB-3312 and binimetinib):
      • Naïve to MEK, ERK, or SHP2 inhibitors.
      • Have provided a formalin fixed tumor tissue sample (collected within ≤18 months) from a biopsy of a tumor lesion either at the time of or after the diagnosis of metastatic disease has been made.
      • KRAS G12D or G12V mutation identified through local or central laboratory testing using archival tissue or liquid biopsy.
        • If possible, at least 10 patients with the G12V mutation in each cohort will be enrolled.
        • PDAC and mCRC are metastatic in nature.
    • Cohort B1 (PDAC):
      • Participants must have histologically or cytologically confirmed PDAC.
      • Received only 1 previous line of standard systemic therapy for metastatic disease. Must either demonstrate progression or become intolerant to the previous line of therapy.
    • Cohort B2 (mCRC):
      • Participants must have histologically or cytologically confirmed mCRC.
      • Received at least 2 and no more than 3 previous lines of standard systemic therapy for metastatic disease. Must either demonstrate progression or become intolerant to the previous line of therapy.
• Participants with a life expectancy ≥3 months.
• Participants must have at least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Tumor lesions that have been irradiated ≥4 weeks before the start of treatment, and have subsequently had documented progression, may be chosen as target lesions in the absence of measurable lesions that have not been irradiated.
• Participants whose laboratory data at Screening meet the following criteria:
  • Absolute neutrophil count ≥1.5 × 109 /L.
  • Platelets ≥150 × 109 /L.
  • Hemoglobin ≥9 g/dL.
  • Albumin ≥3.5 g/dL.
  • Lymphocyte count ≥0.5 × 109 /L.
  • Serum bilirubin ≤1.5 × upper limit of normal (ULN), or ≤ 3.0 × ULN for subjects with Gilbert’s Syndrome.
  • AST and ALT within normal limits.
  • International normalization ratio (INR) 6 weeks prior to Screening.
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to study entry. Women of non-childbearing potential will have had at least 12 continuous months of natural (spontaneous) amenorrhea, and an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms), or have had surgical bilateral oophorectomy, hysterectomy, or bilateral tubal ligation >6 weeks prior to Screening.
• Male or female participants: Male participants with female partners of childbearing potential and female participants of childbearing potential are required to use 2 forms of acceptable contraception (Appendix 13.2), including 1 barrier method, during their participation in the study and for 3 months following last dose. Male participants must also refrain from donating sperm during their participation in the study.
• Participants must be able to swallow and retain orally administered medication.

Exclusion Criteria:

• History (≤3 years) or presence of hematological malignancies.
• History (≤3 years) of other cancer that is histologically distinct from the cancers under study, except for cervical carcinoma in situ, ductal carcinoma in situ, prostatic intraepithelial neoplasia, superficial non-invasive bladder tumors, or curatively treated Stage I non-melanoma skin cancer 3. Known serious allergy to JAB-3312, pembrolizumab, binimetinib, or excipients (e.g., microcrystalline cellulose).
• History (≤6 months before the start of treatment with the study drugs) of severe autoimmune disease (including ≥ Grade 3 or recurrent Grade 2 immune-related adverse events (AEs) of prior immuno-oncology therapy) or autoimmune disorder that requires chronic systemic corticosteroid treatment at immunosuppressive doses (prednisone >10 mg/day or equivalent).
• Brain or spinal metastases, except if treated by surgery, surgery plus radiotherapy or radiotherapy alone, with no evidence of progression or hemorrhage for ≤28 days before the start of treatment with the study drugs, and has not received any systemic corticosteroids for ≥28 days before the start of treatment with the study drugs.
• History (≤6 months before the start of treatment with the study drugs) of pericarditis (any grade) or pericardial effusion (Grade ≥2).
• History (≤6 months before the start of treatment with the study drugs) of interstitial lung disease, radiation pneumonitis which required steroid treatment, idiopathic pulmonary fibrosis, drug-induced pneumonitis, idiopathic pneumonitis, or organizing pneumonia. Radiation-induced pneumonitis (fibrosis) in the radiation field is permitted.
• History (≤6 months before the first dose) of Grade ≥2 pleural effusion.
• Symptomatic ascites that requires therapeutic intervention within last 3 months before the start of treatment.
• Active infection requiring systemic treatment at the start of treatment in this trial. A washout period of 7 days after the last dose of antibiotics prior to first dose of study drug is required.
• History of seropositive status for human immunodeficiency virus (HIV) at any time before the start of treatment as determined by presence of anti-HIV-1 or anti-HIV-2 antibodies. Note: Testing for seropositive status during Screening will be at the discretion of the investigator in participants without previously reported results.
• Has active hepatitis B, or hepatitis C infection.
  • Note: Participants will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at Screening. Note: Participants with hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction (PCR) that is below the limit of detection) are permitted. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Note: Participants who are hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) may be enrolled into the study. Participants with controlled infections must undergo periodic monitoring of HCV RNA per treating physician.
• History (≤6 months before the start of treatment) of any severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator and sponsor, could affect the patient’s participation in the study such as:
  • Nonmalignant illnesses that are uncontrolled or whose control may be jeopardized by this study treatment.
  • Nonmalignant decompensated liver disease.
  • Significant gastrointestinal abnormalities or a chronic condition, including inability to swallow the formulated product, delayed gastric emptying, chronic active Crohn's disease that requires steroid therapy at any dose, refractory nausea and vomiting, and/or prior surgical procedures affecting absorption or requirement for intravenous alimentation.
• History (≤6 months before the start of treatment with the study drugs) of any of the following: acute myocardial infarction, unstable angina pectoris, coronary artery bypass graft, or cerebrovascular accident.
• Participants who have impaired cardiac function or clinically significant cardiac diseases, including any of the following:
  • Significant ventricular or supraventricular arrhythmias (patients with sinus arrhythmia or chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
  • Left ventricular ejection fraction (LVEF) <50% assessed by echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 6 months before the start of treatment with the study drugs and at screening.
  • Resting bradycardia (<50 beats per minute) determined as the mean of 3 heart rate values from the screening triplicate 12-lead electrocardiograms (ECGs) obtained.
  • Other clinically significant heart disease such as congestive heart failure New York Heart Association Class II-IV.
• Participants with QT interval >470 msec at Screening using Fridericia’s formula (QTcF), determined as the mean of 3 QTcF values from the screening triplicate ECG.
• History (≤6 months before the start of treatment with the study drug) of significant eye inflammatory, central serous retinopathy, uveitis, or evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndrome).
• Participants experiencing unresolved Grade >1 toxicity before the start of treatment with the study drug except for hair loss (alopecia), Grade 2 neuropathy (if permitted by the investigator and medical monitor), lymphocytes 0.5 to 0.8 × 109 /L, hemoglobin 9 to 10 g/dL, and hypothyroidism that requires thyroid hormone supplements but is asymptomatic under stable therapy, with thyroid hormone results acceptable to the investigator and medical monitor.
• Participants who are planning to do strenuous exercise after the first dose of study treatment. Strenuous activity should be avoided given its risk for elevated CK while on binimetinib.
• Participants who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis spinal muscular atrophy).
• History (≤6 months before the start of treatment with the study drugs) of malignant biliary obstruction, except for patients with a functioning biliary stent.
• Women who are pregnant or breast-feeding.
• Has received or will receive a live vaccine within 30 days prior to the first administration of study medication. Seasonal flu vaccines that do not contain live vaccine are permitted.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
• History of an allogeneic bone marrow or solid organ transplant.
• Use of systemic anticancer agent (except for antiandrogen therapy for prostate cancer, therapy for bone metastases or cancer-related hypercalcemia) or investigational drug is prohibited ≤28 days for biologics and intravenous chemotherapy, or ≤14 days or 5 half-lives for small molecules, whichever is longer, prior to the first dose of JAB-3312.
• History of radiation therapy ≤28 days prior to the first dose of JAB-3312.
• Use of drugs known to be moderate or strong CYP3A4 inhibitors or inducers or sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index is prohibited ≤14 days before the start of treatment with the study drug until the endof-treatment visit. Some of these medications may be allowed at the investigator’s discretion after approval by the medical monitor.
• Use of herbal drugs and supplements known to be moderate or strong CYP3A4 inhibitors or inducers or sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index is prohibited ≤14 days before the start of treatment with the study drug until the end-of-treatment visit. These herbal medications include but are not limited to: St. John's wort, cannabis (including “medical marijuana”), kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cumin, and ginseng.
• History (≤28 days before the start of treatment with the study drugs) of major surgery or trauma or likelihood to require surgery at any time until the permanent discontinuation of treatment (the significance will be determined by the investigator after consultation with the medical monitor).
• Participants who start erythropoietin or G-CSF, pegfilgrastim, or filgrastim ≤4 weeks before start of treatment with the study drug.
• History (≤4 weeks before the first dose of JAB-3312) of transfusion of whole blood, red blood cells or platelet packets.
• History (≤2 weeks before the start of treatment with the study drugs) of medications with known risk of Torsades de Pointes (cardiac arrhythmia due to drug-induced QTc prolongation).
• Use of H2-receptor antagonists, proton pump inhibitors, and/or intraluminal antacids within 3 days or 5 half-lives (whichever is longer) prior to starting JAB-3312.