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.
- 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
- 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).
- 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
- 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
- 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
- Current active liver or biliary disease (except for Gilbert's syndrome or asymptomatic
gallstones, liver metastases, or otherwise stable chronic liver disease per
- 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
- 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.