First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors
Condition: Neoplasms, Pancreatic
MeSH terms: Pancreatic Neoplasms
Intervention: GSK3145095; Pembrolizumab
Intervention description: GSK3145095 will be available as capsule (size 1 containing 5 to 25 mg GSK3145095 and size 0 containing 25 to 75 mg GSK3145095) or tablet (25, 50, 200 mg white to slightly covered round/oval shaped coated) for oral administration in the fasted stated with approximately 200 milliliters (mL) of water.; Pembrolizumab will be available as solution for infusion (100 milligrams/ 4 milliliter) at a dose of 200 mg via IV infusion for 30 minutes (given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted i.e., infusion time is 25 to 40 minutes).
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Part 1 dose escalation will administer escalating doses of GSK3145095 as monotherapy only. Part 2 will combine escalating doses of GSK3145095 with 200 mg pembrolizumab. Dose escalation of GSK3145095 will begin at least one level below the highest dose shown to have an acceptable toxicity profile in at least 3 subjects in Part 1. Part 3 will enroll subjects treated with one or more dose levels of GSK3145095 in combination with 200 mg pembrolizumab. Part 4 will investigate the combination of additional anticancer agents with one or more doses of GSK3145095 identified as safe in Part 1.
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Anticancer Agents; FTIH; Pembrolizumab; Rip1K; GSK3145095; Dose Escalation; Immunotherapy resistance; Dose Expansion; RECIST 1.1; Advanced solid tumors; Innate immunity

Summary:

      In an unbiased CRISPR screen, RIPK1 was identified as a top gene contributing to
      immunotherapy resistance. In addition, RIPK1 has been reported to drive pancreatic
      oncogenesis. In murine models, inhibition of RIPK1 kinase activity in the pancreatic tumor
      microenvironment leads to the replacement of tumor-permissive myeloid infiltrates with innate
      cells that promote an effective antitumor response by adaptive cells. The investigators
      hypothesize that inhibition of RIPK1 in human pancreatic cancer subjects will modulate the
      immune infiltrate to sensitize tumors to checkpoint blockade.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must provide signed, written informed consent.

          -  Male and female subjects, age >=18 years (at the time consent is obtained). a) Male
             subjects are eligible to participate if they agree to the following during the study
             treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the
             last dose of study treatment: Refrain from donating sperm, be abstinent from
             heterosexual or homosexual intercourse as their preferred and usual lifestyle
             (abstinent on a long term and persistent basis) and agree to remain abstinent or must
             agree to use contraception/barrier: male condom and female partner to use an
             additional highly effective contraceptive method with a failure rate of <1 percent per
             year. b) female subjects are eligible to participate if they are not either pregnant
             or breastfeeding, and at least one of the following conditions applies: is not a woman
             of childbearing potential (WOCBP), is a WOCBP and using a contraceptive method that is
             highly effective (with a failure rate of <1 percent per year), with low user
             dependency during the study treatment period and for at least 15 days (Part 1) and 120
             days (Parts 2-4) after the last dose of study treatment and agrees not to donate eggs
             (ova, oocytes) for the purpose of reproduction during this period. The investigator
             should evaluate the effectiveness of the contraceptive method in relationship to the
             first dose of study treatment. Hormonal contraception may be susceptible to
             interaction with the study drug, which may reduce the efficacy of the contraceptive
             method. Therefore, a barrier method is also required for subjects using a hormonal
             option (including hormonal intrauterine device [IUD], oral contraceptive pills/ patch/
             vaginal inserts, and hormonal implants) and both highly effective methods of
             contraception should be utilized during the treatment period and for at least 15 days
             (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment.If a highly
             effective non-hormonal method is used, then only one method of contraception is
             required (by a female participant or partner of a male participant; in either
             situation the male partner must still use a male condom in addition) during the
             treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the
             last dose of study treatment. A WOCBP must have a negative highly sensitive pregnancy
             test (urine or serum) as required by local regulations) within 24 hours before the
             first dose of study intervention. If a urine test cannot be confirmed as negative
             (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the
             subject must be excluded from participation if the serum pregnancy result is positive.
             If the subject hasn't been on an acceptable method of contraception for at least 2
             weeks prior to start of therapy, pregnancy testing must be done weekly for the first
             month of treatment. Additional requirements for pregnancy testing during and after
             study treatment. The investigator is responsible for review of medical history,
             menstrual history, and recent sexual activity to decrease the risk for inclusion of a
             woman with an early undetected pregnancy.

          -  Histological documentation of locally advanced, recurrent or PDAC (Part 1), non-small
             cell lung cancer (NSCLC), triple negative breast cancer (TNBC), or melanoma (Part 2)
             that has progressed after standard therapy appropriate for the specific tumor type, or
             for which standard therapy has proven to be ineffective, intolerable, or is considered
             inappropriate. Subjects should have received at least one, but not more than 2 prior
             lines of therapy for advanced disease including both standards of care and
             investigational therapies. Subjects whose cancers harbor molecular alterations for
             which targeted therapy is standard of care should have received health
             authority-approved appropriate targeted therapy for their tumor types before
             enrollment.

          -  All subjects in Parts 1 and 2 must consent to provide a fresh biopsy during screening
             of a primary tumor lesion or from other metastases (e.g. liver, lung, etc.), and a
             second biopsy after approximately 5 weeks of treatment.

          -  Measurable disease per RECIST version 1.1. Palpable lesions that are not measurable by
             radiologic or photographic evaluations may not be utilized as the only measurable
             lesion. Subjects are encouraged to provide a pre-Baseline scan (within 24 weeks before
             the Baseline scan) to support exploratory investigation of tumor growth kinetics.

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1.

          -  Life expectancy of at least 12 weeks.

          -  Adequate organ function.

          -  QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 milliseconds
             (or QTcF <480 milliseconds for subjects with bundle branch block).

        Exclusion Criteria:

          -  Prior treatment with the following agents: Agents affecting tumor associated
             macrophage function or number, including but not limited to inhibitors of
             Receptor-interacting protein 1 (RIP1), Receptor-interacting protein 3 (RIP3), Colony
             stimulating factor 1 receptor (CSFR-1), C-C chemokine receptor type 2 (CCR2), and
             Cluster of differentiation 40 (CD40). Other anticancer therapy, including
             chemotherapy, targeted therapy, and biological therapy, within 14 days or 5 half-lives
             (from last dose of prior treatment to first dose of GSK3145095), whichever is shorter.
             Prior radiation therapy is permissible if at least one non-irradiated measurable
             lesion is available for assessment via RECIST version 1.1. No washout after palliative
             radiation is required. Investigational therapy within 14 days or 5 half-lives (from
             last dose of prior treatment to first dose of GSK3145095), whichever is shorter.

          -  Prior allogeneic or autologous bone marrow transplantation or other solid organ
             transplantation.

          -  Toxicity from previous treatment: Subjects whose toxicity related to prior treatment
             has not resolved to <=Grade 1 (except alopecia, hearing loss, Grade <=2 neuropathy or
             endocrinopathy managed with replacement therapy) are not eligible.

          -  Malignancy other than disease under study, except as noted: Subject with any other
             malignancy from which the subject has been disease-free for more than 2 years and, in
             the opinion of the principal investigators and GlaxoSmithKline (GSK) Medical Monitor,
             will not affect the evaluation of the effects of this clinical trial treatment on
             currently targeted malignancy, can be included in this clinical trial.

          -  Major surgery <=4 weeks before the first dose of study treatment. Subjects must have
             also fully recovered from any surgery (major or minor) and/or its complications before
             initiating study treatment.

          -  Active autoimmune disease that has required systemic treatment within the last 2 years
             (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement
             therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
             systemic treatment.

          -  Concurrent medical condition requiring the use of systemic immunosuppressive
             medications within 28 days before the first dose of study treatment. Physiologic doses
             of corticosteroids for treatment of endocrinopathies or steroids with minimal systemic
             absorption, including topical, inhaled, or intranasal corticosteroids, may be
             continued if the subject is on a stable dose.

          -  Active infection (including active herpes zoster infection), known human
             immunodeficiency virus infection, or positive test for hepatitis B surface antigen or
             hepatitis C.

          -  Current active liver or biliary disease (except for Gilbert's syndrome or asymptomatic
             gallstones, liver metastases, or otherwise stable chronic liver disease per
             investigator assessment).

          -  Known current drug or alcohol abuse.

          -  Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel
             disease, intra-abdominal abscess, or gastrointestinal obstruction.

          -  Receipt of any live vaccine within 4 weeks before starting study treatment.

          -  Recent history of allergen desensitization therapy within 4 weeks before starting
             study treatment (applies to subjects enrolled in Parts 2 and 3 only).

          -  History or evidence of cardiovascular risk including any of the following: recent
             (within the past 6 months) history of serious uncontrolled cardiac arrhythmia or
             clinically significant electrocardiogram (ECG) abnormalities including second degree
             (Type II) or third degree atrioventricular block. Documented cardiomyopathy,
             myocardial infarction, acute coronary syndromes (including unstable angina pectoris),
             coronary angioplasty, stenting, or bypass grafting within the past 6 months before
             beginning screening. Documented congestive heart failure (Class II, III, or IV) as
             defined by the New York Heart Association functional classification system. Recent
             (within the past 6 months) history of symptomatic pericarditis.

          -  Current or history of idiopathic pulmonary fibrosis, interstitial lung disease, or
             organizing pneumonia.

          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis.

          -  Recent history (within 14 days) of ascites or pleural effusions requiring drainage.

          -  Any serious and/or unstable pre-existing medical, psychiatric disorder, or other
             condition that could interfere with the subjects safety, obtaining informed consent,
             or compliance to the study procedures.

          -  Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or
             child) who is investigational site or sponsor staff directly involved with this trial,
             unless prospective Institutional Review Board (IRB) approval (by chair or designee) is
             given allowing exception to this criterion for a specific subject.