GLP-1 RA Plus SOC Treatment in First-line, Metastatic Pancreatic, Colorectal, or Hepatocellular Cancer

• Histological or cytological diagnosis of pancreatic adenocarcinoma or colorectal adenocarcinoma. Previous tumor tissue testing is acceptable. Please refer to the "additional HCC cohort criteria" below.
• The subject has disease that is not amenable to curative-intent management (e.g., oligometastatic disease)
• Measurable disease per RECIST v1.1 as determined by the investigator

• Patients must be appropriate candidates for first-line, SOC treatment.

  • SOC treatment as defined by NCCN® guidelines or institutional standard is allowable, however, options restricted to:

    • Colorectal: FOLFOX or FOLIFIRI +/- bevacizumab
    • Pancreatic: mFOLFIRINOX
    • HCC: Tremelimumab/Durvalumab
  • Patients are eligible who received prior perioperative chemotherapy for curative intent treatment and recurred ≥ 6 months since last dose of chemotherapy.
• ≥ 18 years old on day of consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate archival frozen or fixed tissue available from primary or metastatic site for genotypic analysis (at least 15 unstained slides and/or tumor block)

• Adequate hematologic and organ function laboratory values as follows:

  • The ANC ≥ 1500/mm3 without colony stimulating factor support;
  • Platelets ≥ 75,000/mm3;
  • Hemoglobin ≥ 9 g/dL;
  • Bilirubin ≤ 1.5 ´ the ULN. For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL;
  • Serum albumin ≥ 2.8 g/dl;
  • ALT and AST ≤ 3.0 ´ ULN;

  • Serum creatinine ≤ 1.5 ´ ULN or creatinine clearance (CrCl) ≥ 40 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used:

    • Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72);
    • Female: Multiply above result by 0.85;
• The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control or practice abstinence during the study and for 4 months after the last dose of study drug(s);

Additional Inclusion Criteria for HCC Cohort ONLY:

• Histologically or radiologically confirmed hepatocellular carcinoma (per AASLD/EASL criteria)
• Unresectable or advanced HCC not amenable to curative surgery or locoregional therapy.
• Barcelona Clinic Liver Cancer (BCLC) stage B or C.
• Child-Pugh Score Class A; or Child-Pugh Class B7 or B8 at discretion of treating physician

• Patients with HBV infection, characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV deoxyribonucleic acid (DNA) (≥10 IU/mL or above the limit of detection per local or central lab standard), must be treated with antiviral therapy, as per institutional practice to ensure adequate viral suppression (HBV DNA \<2000 IU/mL) before enrolment. Patients must remain on antiviral therapy for the duration of their participation in the EAP and for 6 months after the last dose of EAP medication. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (\<10 IU/mL or under the limit of detection per local or central lab standard) do not require anti-viral therapy before enrolment. These participants will be tested at every cycle to monitor HBV DNA levels and initiate anti-viral therapy if HBV DNA is detected (≥10 IU/mL or above the limit of detection per local or central lab standard). HBV DNA detectable patients must initiate and remain on anti-viral therapy for time they are on the EAP and for 6 months after the last dose of EAP medication.

  o Note: Testing required for subjects with a known history otherwise not required.

• Patients with HCV infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrolment (management of this disease is per local institutional practice).

Exclusion Criteria

• The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) for metastatic and/or unresectable disease.
• BMI \< 25 kg/m2
• For colorectal cancer only - Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) tumors.
• For colorectal cancer only - BRAF V600E mutant tumors.
• A personal or family history of medullary thyroid cancer (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2).
• A prior hypersensitivity reaction to semaglutide or any of the excipients in WEGOVY®. Serious hypersensitivity reaction, including anaphylaxis and angioedema, have been reported with WEGOVY®.
• Cachexia
• Subjects on insulin.
• Subjects with a history of diabetic retinopathy
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment

• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

  o Cardiovascular disorders including:

  • For patients being considered for bevacizumab (or bevacizumab biosimilar) only:
• Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment;

• thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (eg, vena cava filter) within 6 months before the first dose of study treatment.

  • Any of the following within 6 months before the first dose of study treatment:
• unstable angina pectoris;
• clinically-significant cardiac arrhythmias;
• stroke (including transient ischemic attack (TIA), or other ischemic event);

• myocardial infarction;

  • GI disorders particularly those associated with a high risk of perforation or fistula formation including:

    • Unresolved abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess.
    • Uncontrolled nausea, vomiting, or abdominal pain.
  • Other clinically significant disorders that would preclude safe study participation
• Major surgery within 8 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• Females who are known or suspected to be pregnant or lactating. Women of childbearing potential must have a negative serum pregnancy test result within screening.
• Female patients planning on becoming pregnant while on study.
• Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment.
• Male subjects unwilling to abstain from donating sperm during treatment.
• Inability to comply with self-administration of GLP-1 RA subcutaneous injections.
• Subject has known sensitivity to any of the products or components to be administered during dosing.
• Concurrent use of other semaglutide containing products or any other GLP-1 receptor agonist.
• Diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.
• Subject likely to not be available to complete all protocol-required study visits or procedures and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.
• History or evidence of any other clinically significant disorder, condition or disease that in the opinion of the investigator, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.

Additional Exclusion Criteria for HCC Cohort ONLY:

• Child-Pugh Score Class B9; or Child-Pugh Class C
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 days of the first dose of EAP treatments.
• History of allogenic organ transplantation (e.g., liver transplant).
• History of hepatic encephalopathy within the past 12 months or requirement for medications to prevent or control encephalopathy (e.g., no lactulose, rifaximin, etc if used for purposes of hepatic encephalopathy.
• Clinically meaningful ascites, defined as any ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 2 months before the first EAP treatment dose. Patients on stable doses of diuretics for ascites for ≥2 months are eligible.
• Patients with main portal vein thrombosis (i.e., thrombosis in the main trunk of the portal vein, with or without blood flow) on baseline imaging.

• Active or previously documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [except for diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). Patients without active disease in the last 5 years are excluded unless discussed with the Treating Physician and considered appropriate for EAP participation. The following are exceptions to this criterion:

  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients with celiac disease controlled by diet alone

• Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV). HBV positive (presence of HbsAg and/or anti-HBcAb with detectable HBV DNA); HCV positive (presence of anti-HCV antibodies); HDV positive (presence of anti-HDV antibodies).

  o Note: Testing required for subjects with a known history otherwise not required.

• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• History of active primary immunodeficiency.

• Current or prior use of immunosuppressive medication within 14 days before the first dose of EAP treatment. The following are exceptions to this criterion:

  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  • Steroids as pre-medication for hypersensitivity reactions (e.g., CT scan pre-medication)
• Receipt of live attenuated vaccine within 30 days before first dose of treatment. Note: patients, if enrolled, should not receive live vaccine while receiving study treatment, and up to 30 days after the last dose of study treatment.
• Previous randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
• Patients who have received anti-PD-1, anti-PD-L1, or anti-CTLA-4 before the first dose of EAP treatment.