A Phase 1 Study to Evaluate the Safety, Tolerability,Pharmacokinetics, and Pharmacodynamics of GS-5745 as Monotherapy and in Combination with Chemotherapy in Subjects with Advanced Solid Tumors
- Zale Lipshy University Hospital
This is an open-label, multicenter, sequential dose-escalation, and expansion study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of GS-5745 alone and in combination with chemotherapy. The study will be conducted in 2 parts (Parts a and B).
Cohorts of subjects with advanced solid tumors who have failed or are intolerant to standard therapy or for whom no standard therapy exists will be sequentially enrolled at progressively higher dose levels to receive GS-5745 as monotherapy via intravenous (iV) infusion every 2 weeks (Q2W). Dose escalation [3+3] will be performed with cohort sizes of 3 to 6 subjects. a single subject will initially be enrolled into the first dosing cohort to evaluate any unexpected adverse effects. Provided that there are no significant safety signals up to 24 hours post-dose, the
remaining 2 subjects will be dosed. The starting dose will be 200 mg. Subsequent doses of 600 and 1800 mg are planned. The safety and tolerability of each dose level will be assessed after all subjects in the cohort have been followed for at least 28 days after the first infusion of GS-5745. Cohort dose escalation will occur
if no subjects experience dose limiting toxicities (DLT) during the first 28 days of study drug dosing. if one subject within the initial cohort of 3 subjects experiences a DLT during the first 28 days of study drug dosing, an additional 3 subjects will be enrolled at the same dose level. if no DLTs are observed in the additional 3 subjects, dose escalation will occur. if 2 or more subjects experience DLTs within the first 28 days, dose de-escalation to an intermediate dose will occur. Specifically, if 2 or more subjects experience DLTs at 1800 mg, then 1200 mg
will be explored. if 2 or more subjects experience DLTs at 600 mg, then 400 mg will be explored. The maximum tolerated dose (MTD) is the highest dose level with a subject incidence of DLTs during the first 28 days of study drug dosing of 0 or 1 out of 6.
a DLT is a toxicity defined below considered possibly related to GS-5745 occurring during the DLT assessment window (Day 1 through Day 29) in each dose escalation cohort.
* Grade 4 neutropenia (absolute neutrophil count [anC]
[Less Than] 500/[MiCRo-SYMBoL]L) for [Greater Than] 7 days, or febrile neutropenia (anC
[Less Than] 1000/[MiCRo-SYMBoL]L with fever [Greater Than] 101oF [38.5oC])
* Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia
associated with bleeding
* Grade 3 or 4 non-hematologic toxicity (excluding rash,
nausea, diarrhea, and vomiting if controlled with standard
* Treatment delay of [GreaterThanorequalTo] 14 days due to unresolved toxicity
* non-hematologic toxicity of [GreaterThanorequalTo] Grade 2 (at any time during treatment) that, in the judgment of the investigators and the Medical Monitor, is dose-limiting.
* For certain toxicities such as laboratory assessments without a clear clinical correlate, a discussion between the investigator, Medical Monitor, and the Sponsor may take place to determine if this adverse event (ae) should be assessed as a DLT necessitating dose reduction.
after determination of MTD, Part B will commence - dose expansion phase. after all subjects in the dose escalation portion of part a have completed the 28-day DLT period, approximately 70 to 145 subjects with advance pancreatic adenocarcionma, lung adenocarcinoma, lung squamous cell carcinoma or esophagogastric adenocarcinoma will be recruited and enrolled to receive GS-5745 intravenously every 2-3 weeks in combination with chemotherapy. The subjects that particpated in Part a will not participate in Part B.
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1. Male or female >= 18 years of age
2. Part A: histologically or cytologically confirmed advanced malignant solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy is available
3. Part B Pancreatic Adenocarcinoma:
a. Presence of histologically confirmed inoperable locally advanced or metastatic pancreatic adenocarcinoma
4. Part B NSCLC:
a. Stage IIIB with malignant pleural effusion/pleural seeding or stage IV histologically confirmed NSCLC
b. Absence of known EGFR (Epidermal Growth Factor Receptor) mutation
c. Absence of known translocation or inversion events involving the ALK gene locus (resulting in EML4-ALK fusion)
5. Part B Esophagogastric Adenocarcinoma:
a. Histologically confirmed inoperable advanced gastric adenocarcinoma (including adenocarcinoma of the gastrooesophageal junction) or relapsed gastric adenocarcinoma
b. Human Epidermal Growth Factor Receptor 2 (HER2)-negative tumor (primary tumor or metastatic lesion)
6. All acute toxic effects of any prior antitumor therapy resolved to Grade <= 1 before the start of study drug dosing (with the exception of alopecia [Grade 1 or 2 permitted] and neurotoxicity [Grade 1 or 2 permitted])
7. ECOG Performance Status of <= 1
8. Life expectancy of > 3 months in the opinion of the Investigator
9. Adequate organ function defined as follows:
a. Hematologic: Platelets >= 100 x 109/L; Hemoglobin >= 9.0 g/dL; ANC >= 1.5 x 109/L
b. Hepatic: AST/ALT <= 2.5 x ULN (if liver metastases are present, <= 5 x ULN); Total or conjugated bilirubin <= 1.5 x ULN
c. Renal: Serum Creatinine <= 1.5 x ULN
10. Coagulation: International Normalized Ratio (INR) <= 1.6 (unless receiving anticoagulation therapy). Subjects on full-dose oral anticoagulation must be on a stable dose (minimum duration 14 days). If receiving warfarin, the subject must have an INR <= 3.0 and no active bleeding (ie, no bleeding within 14 days prior to first dose of study drug). Subjects on low molecular weight heparin will be allowed.
11. Female subjects of childbearing potential, willing to use a protocol-recommended method of contraception from the screening visit throughout the study treatment period and for 90 days following the last dose of study drugs. Note: A female subject is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional postmenopausal range and a negative serum or urine [BETA]-HCG), or is menopausal (age >= 55 years with amenorrhea for >= 6 months).
12. Male subjects of childbearing potential having intercourse with females of childbearing potential, willingness to use a protocol-recommended method of contraception from the start of study drug, throughout the study treatment period, and for 90 days following the last dose of study drugs, and to refrain from sperm donation from the start of study drug, throughout the study treatment period, and for 90 days following the last dose of study drugs. Note: A male subject is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) agonist (eg, goserelin acetate [Zoladex(RegisteredTM)]), leuprolide acetate [Lupron(RegisteredTM)]), or triptorelin pamoate [Trelstar(RegisteredTM)]).
13. Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions
14. Evidence of a signed informed consent form