Clinical Trials

Inclusion Criteria:

• Written informed consent, according to local guidelines, signed and dated by the patient prior to the performance of any study-specific procedures, sampling, or analyses.
• Patient 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;
  • Prior treatment with PD-1/PD-L1 agents is allowed.
• Cohort B0 (JAB-3312 + binimetinib):
  • Advanced solid tumors with known mutations in KRAS;
  • Naïve to MEK, SHP2, or extracellular signal-regulated kinase (ERK) inhibitors.
• Cohort C0 (JAB-3312 + sotorasib):
  • Any KRAS-G12C mutant tumors;
  • Prior treatment with KRAS G12C inhibitors is allowed.
• Cohort D0 (JAB-3312 + Osimertinib):
  • Advanced NSCLC with sensitive EGFR mutation including EGFR exon 21 L858R or exon 19 deletion mutation, or T790M mutation;
  • Prior treatment with osimertinib is allowed.

Dose Expansion Phase

• Cohorts A1, A2, A3 (JAB-3312 + pembrolizumab):
  • Naïve to anti-PD-1/PD-L1 agents (A1 and A2 cohort only);
  • 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 epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) translocation, or other actionable molecular alterations that can be treated with Food and Drug Administration-approved targeted agents.
  • PD-L1 tumors expression of 1% or greater (tumor proportion score [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 (combined positive score [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;
  • Received at least 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 or ERK 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 mutation identified through local or central laboratory testing using archival tissue or liquid biopsy;
  • Pancreatic ductal adenocarcinoma (PDAC) and mCRC are metastatic in nature.
• Cohort B1 (PDAC):
  • Patients 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):
  • Patients must have histologically or cytologically confirmed mCRC;
  • Received at least 2 and no more than 4 previous lines of standard systemic therapy for metastatic disease. Must either demonstrate progression or become intolerant to the previous line of therapy.
• Cohort C1 (JAB-3312 + sotorasib) (NSCLC):
  • Advanced NSCLC with KRAS G12C mutation;
  • Received at least one prior systemic therapy;
  • Naïve to KRAS G12C inhibitor treatment.
• Cohort D1 (JAB-3312 + osimertinib) (NSCLC):
  • Prior response to osimertinib based treatment and followed by radiological confirmed disease progression;
  • Osimertinib must have been included as the last systemic therapy as first line or second line prior to study enrollment;
  • Platinum-based treatment naïve advanced NSCLC patients;
  • Histologic transformation from NSCLC to SCLC after osimertinib treatment is excluded.
• Patients with a life expectancy ≥ 3 months.
• Patients 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.
• Patients whose laboratory data at screening meet the following criteria:
  • ANC ≥ 1.5 × 10^9 /L;
  • Platelets ≥ 150 × 10^9 /L;
  • Hemoglobin ≥ 9 g/dL;
  • Albumin ≥ 3.5 g/dL;
  • Serum bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for subjects with Gilbert’s Syndrome;
  • AST and ALT within normal limits for patients without liver metastasis, ≤ 2.5 × ULN for patients with liver metastasis;
  • International normalization ratio (INR) 6 weeks prior to Screening;
  • Kidney function is normal with an estimated glomerular filtration rate > 60 mL/min (measured using Cockcroft-Gault equation).
• 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 patients: Male patients with female partners of childbearing potential and female patients of childbearing potential are required to use 2 forms of acceptable contraception, including 1 barrier method, during their participation in the study until 3 months following the last dose of JAB-3312 or binimetinib, or 4 months following the last dose of pembrolizumab, whichever is longer. Male patients must also refrain from donating sperm during their participation in the study until 3 months following the last dose of JAB-3312 or binimetinib, or 4 months following the last dose of pembrolizumab, whichever is longer.
• Patients 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.
• Known serious allergy to JAB-3312, pembrolizumab, binimetinib, sotorasib, osimertinib or excipients (e.g., microcrystalline cellulose).
• History (≤ 6 months before the start of study treatment) 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 (for cohort D0 and D1, patient is also eligible if brain or spinal metastases are well controlled by prior treatment of osimertinib), with no radiographic evidence of progression or hemorrhage for ≥ 28 days before the start of study treatment and has not received any systemic corticosteroids for ≥ 28 days before the start of study treatments.
• History (≤ 6 months before the start of study treatment) of pericarditis (any grade) or pericardial effusion (Grade ≥ 2).
• History (≤ 6 months before the start of study treatment) 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 (≤ 4 weeks before the first dose of study treatment) of Grade ≥ 2 pleural effusion.
• Symptomatic ascites that requires therapeutic intervention within last 4 weeks before the start of treatment.
• Active infection requiring systemic treatment within 7 days prior to the first dose of study treatment.
• 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 patients without previously reported results.
• Has active hepatitis B, or hepatitis C infection.
  • Note: Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at screening.
  • Note: Patients with hepatitis B (hepatitis B virus surface antigen positive [HepBsAg+]) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction [PCR] that is below the limit of detection) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA.
  • Note: Patients 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. Patients with controlled infections must undergo periodic monitoring of HCV RNA per treating physician.
• History 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 (IV) alimentation.
• History (≤ 6 months before the start of study treatment) of any of the following: acute myocardial infarction, unstable angina pectoris, coronary artery bypass graft, or cerebrovascular accident.
• Patients 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 study treatments and at screening;
  • Resting bradycardia (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 study treatment) 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).
• Patients experiencing unresolved Grade >1 toxicity before the start of study treatment except for hair loss (alopecia), Grade 2 neuropathy (if permitted by the investigator and medical monitor), 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, and Grade > 1 abnormal laboratory results which are not considered clinically significant by the investigator and medical monitor.
• Patients who are planning to do strenuous exercise after the first dose of study treatment. Strenuous activity should be avoided given its risk for elevated creatine kinase (CK) while on binimetinib.
• Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis spinal muscular atrophy).
• 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 treatment. 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 study. Prior and Concomitant Therapy. 
• History of an allogeneic bone marrow or solid organ transplant.
• Use of systemic anticancer agent (except for hormonal therapy for prostate cancer and breast cancer, therapy for bone metastases or cancer-related hypercalcemia) or investigational drug is prohibited ≤ 28 days for biologics and IV chemotherapy, or ≤ 14 days or 5 half-lives for small molecules, whichever is shorter prior to the first dose of JAB-3312.
• History of therapeutic radiation ≤ 28 days, or palliative radiation ≤ 14 days prior to the first dose of JAB-3312.
• Use of drugs known to be moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers or sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index is prohibited ≤ 14 days or 5 half-lives, whichever is longer, before the start of study treatment until the end-of-treatment (EOT). 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 or 5 half-lives, whichever is longer, before the start of study treatment until the EOT. 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. Some of these medications may be allowed at the investigator’s discretion after approval by the medical monitor.
• History (≤ 28 days before the start of study treatments) 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).
• Patients who start erythropoietin or granulocyte colony-stimulating factor, pegfilgrastim, or filgrastim ≤ 4 weeks before start of study treatment.
• History (≤ 4 weeks before the first dose of JAB-3312) of transfusion of whole blood, red blood cells or platelet packets.
• History (≤ 2 weeks or 5 half-lives, whichever is longer, before the start of study treatments) of medications with known risk of Torsades de Pointes (cardiac arrhythmia due to drug-induced QTc prolongation).
• Use of histamine 2 (H2)-receptor antagonists, proton pump inhibitors, and/or antacids within 3 days or 5 half-lives (whichever is longer) prior to starting JAB-3312.

Eligibility last updated 1/7/22. Questions regarding updates should be directed to the study team contact.