| Eligibility |
Inclusion Criteria:
1. Male or female =18 years of age at the time of signing informed consent.
2. Diagnosis of histologically or cytologically confirmed advanced solid tumors
1. Dose Escalation Stage: patients with solid tumors (excluding melanoma and
hepatocellular CR) who have failed all available therapies or are not eligible
for standard of care (SOC).
2. Dose Expansion Stage:
i. Cohort A: Advanced or Metastatic Pancreatic Cancer (pancreatic ductal;
adenocarcinoma) who have failed or are not eligible for SOC; ii. Cohort B: Advanced or
Metastatic Ovarian Cancer of the serous type (ovarian serous adenocarcinoma; ovarian
serous cystadenocarcinoma) who have failed or are not eligible for SOC; iii. Cohort C:
Advanced or Metastatic Biliary Cancer (intrahepatic, extrahepatic, gallbladder) who
have failed or are not eligible for SOC.
3. Eastern Cooperative Oncology Group (ECOG) status of 0-1.
4. Measurable disease per RECIST as assessed by local site investigator/radiologists;
lesions situated in previous irradiated areas are considered measurable if progression
has been demonstrated in such lesions.
5. Patients must have a tumor lesion that can be safely biopsied and agree to provide a
fresh or archival tissue sample prior to treatment initiation and agree to an
on-treatment biopsy. The on-treatment biopsy may be waived for patients in the Dose
Escalation Stage if a biopsy sample is not possible. An archival sample must be =6
months old.
6. Locally advanced, recurrent, or metastatic neoplastic disease that has failed to
respond to standard therapy, is not curable by currently available local therapies, or
for whom no appropriate therapies are available (based on the judgement of the
Investigator.
7. Life expectancy of =3 months in the judgement of the Investigator
8. Adequate hematologic function based on the following:
a. Absolute neutrophil count =1.5 x 109/L b. Platelet count =100 x 109/L c. Hemoglobin
=9.0 g/dL
9. Adequate coagulation parameters based on the following:
a. Prothrombin Time-International Normalized Ratio/partial thromboplastin time
(PT-INR/PTT) < ) <1.5 x ULN, unless coumarin derivatives are used; and b. Partial
thromboplastin time (PTT) or activated partial thromboplastin time (APTT) <1.25 x ULN
(therapeutic anticoagulation.
Note: Anti-coagulation therapy is allowed, if this treatment canpermitted but should
be able to be interrupted for a biopsy as judgedif deemed necessary by the
Investigator).. The coagulation parameters for patients on anti-coagulation will be
interpreted according to expected institutional therapeutic parameters.
10. Adequate hepatic function based on the following:
a. Total bilirubin <1.5 × upper limit of normal (ULN) (unless elevated due to
Gilbert's syndrome [=3.0 × ULN]) and/or isolated elevations of indirect bilirubin are
eligible for study participation; b. Alanine aminotransferase (ALT)/aspartate
aminotransferase (AST) =2.5 x ULN (=5 × ULN for patients with known hepatic
metastases).
11. Adequate renal function based on serum creatinine clearance =45 mL/min (normal to
moderate renal impairment) as determined by Cockcroft-Gault equation may be included
in both the Dose Escalation and Dose Expansion stages.
12. Female patients of childbearing potential must have a negative pregnancy test. For
women of childbearing potential (WCBP), defined as a sexually mature woman who has not
undergone surgical sterilization or who has not been naturally post-menopausal for at
least 12 consecutive months for women >55 years of age, a negative serum or urine
pregnancy test must be obtained within 72 hours before first treatment. WCBP should be
placed on effective birth control directly after testing negative for pregnancy; if
not, then WCBP should have a pregnancy test on Day 1 of every dosing cycle, prior to
drug administration. Any positive or indeterminant urine pregnancy test (UPT) result
must be confirmed by serum pregnancy test.
13. Female patients of childbearing potential must use a highly effective mode of
contraception or abstain from heterosexual activity for the duration of the trial and
for 120 days following the last dose of study medication. Highly effective
contraception includes oral hormonal contraceptives, hormonal contraceptive implant,
injection or patch, intrauterine device, or complete abstinence from sexual
intercourse.
14. Male patients must agree to use highly effective contraception. Sexually active males
who have not had a vasectomy, and whose partner is reproductively capable, must agree
to abstain from sexual intercourse or use barrier contraception from Screening through
120 days after their last dose of study treatment.
15. Ability to adhere to the study visit schedule and all protocol requirements.
Exclusion Criteria:
1. Major surgery within 4 weeks prior to Screening. Major surgery is any invasive
operative procedure in which a more extensive resection is performed, e.g. a body
cavity is entered, organs are removed, or normal anatomy is altered. In general, if a
mesenchymal barrier is opened (pleural cavity, peritoneum, meninges), the surgery is
considered major. Minimally invasive (laparoscopic) procedures are not considered
major surgery, unless considered high risk and requiring extended (greater than over-
night observation).
2. Prior radiotherapy within 2 weeks of start of study treatment. Patients must have
recovered from all radiation-related toxicities, not require corticosteroids for their
radiation therapy, and no history of radiation pneumonitis. A 1-week washout is
permitted for palliative radiation (=2 weeks of radiotherapy) to non-central nervous
system disease.
3. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal therapy, targeted
therapy, or investigational agents within five half-lives or four weeks, whichever is
shorter, prior to administration of the first dose of study treatment. Hormonal
therapy as maintenance when there is no evaluable cancer is allowed.
4. Active CNS metastases; however, patients who have undergone radiation and/or surgery
for the treatment of CNS metastases, who are neurologically stable, and who are no
longer taking pharmacologic doses of corticosteroids are eligible; patients with
leptomeningeal metastases are not eligible.
5. Primary CNS malignancy.
6. Evidence of metastatic ileus on CT.
7. Severe gastrointestinal conditions such as clinical or radiological evidence of bowel
obstruction within 4 weeks prior to study entry;
8. Known active Infection with human immunodeficiency virus (HIV), hepatitis B (HBV), or
hepatitis C virus (HCV):
a. Patients with HIV are excluded.
a.b. Patients who are hepatitis B surface antigen positive are eligible if they have
received hepatitis B virus antiviral therapy for at least 4 weeks and have
undetectable HBV viral load prior to enrollment.
i. Note: Patients should remain on antiviral therapy throughout study intervention and
follow local guidelines for HBV antiviral therapy post completion of study
intervention.
ii. Hepatitis B screening tests are not required unless:
1. Known history of HBV infection, 2. Mandated by local health authority. b.c. Patients
with a history of hepatitis C virus infection are eligible if HCV viral load is
undetectable at Screening.
i. Note: Patients must have completed curative antiviral therapy at least 4 weeks prior to
enrollment.
ii. Hepatitis C screening tests are not required unless: 1. Known history of HCV infection,
2. Mandated by local health authority. 9. Requiring immunosuppressive therapy. 10. Ongoing
systemic bacterial, fungal, or viral infections at Screening;
a. Note: Patients on antimicrobial, antifungal, or antiviral prophylaxis are not
specifically excluded if all other inclusion/exclusion criteria are met.
11. Received a live vaccine within 6 weeks of first dose of study drug. 12. Received a
COVID-19 vaccine less than 1 week prior to dosing (Cycle 1 / Day 1) and/or during the study
received a COVID-19 vaccine or booster less than 3 weeks ahead of a tumor assessment.
13. Baseline QT interval corrected with Fridericia's method (QTcF) >480 ms.
a. Note: Criterion does not apply to patients with a right or left bundle branch block.
14. Female patients who are pregnant or breastfeeding. 15. Concurrent active malignancy
other than non-melanoma skin cancer, carcinoma in situ of the cervix, or prostate
intraepithelial neoplasia.
16. History of interstitial lung disease, drug-induced interstitial lung disease, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active
interstitial lung disease.
17. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia
requiring medication or mechanical control within the last 6 months prior to Screening.
a. Note: Current atrial fibrillation that is on treatment and under control is permitted.
18. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function,
unstable pulmonary condition including pneumonitis and/or interstitial lung disease,
uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that
would, in the Investigator's judgment, increase the risk to the patient associated with his
or her participation in the study.
|
