| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of this study are:
Phase 1b Dose Escalation
• Characterize the safety and tolerability of GS-4224 in subjects with advanced solid tumors
• Determine the MTD and RP2D of GS-4224 in subjects with advanced solid tumors
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
Phase 1b Dose Escalation
• Evaluate the PK of GS-4224 in subjects with advanced solid tumors
Phase 2 Dose Expansion
• Evaluate the safety and tolerability of GS-4224 in subjects with advanced solid tumors
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Dose Escalation Biopsy Substudy within section 3.8.2 protocol Am5 dated 2 October 2020
The specimens collected for the Dose Escalation Biopsy Substudy will be used to assess tumor PD-L1 target occupancy, expression of genes related to immune system activity and tumor biology, tumor infiltrating lymphocytes by immunohistochemistry (IHC), and the frequency and identity of tumor mutations
Dose Expansion Biopsy (Optional Assessment) within section 3.8.3 protocol Am 5, dated 2 October 2020
For the Phase 2 cohort, subjects must have available sufficient and adequate formalin-fixed tumor tissue sample preferably from a biopsy of a tumor lesion obtained either at the time of or after the diagnosis of advanced disease has been made and from a site not previously irradiated. Alternatively, subjects must agree to have a biopsy taken prior to entering the study to provide adequate tissue. Subjects with biopsy accessible tumors may also undergo optional post treatment tumor biopsies at Cycle 3 and at EOT. Subjects must agree to and give a separate, specific written consent to provide baseline, on-treatment, and/or EOT biopsies if medically feasible. Biopsies at Cycle 3 should be collected after radiographic tumor scans scheduled for that cycle have been completed.
The exploratory objectives of this study are:
• To evaluate the pharmacodynamics, including target occupancy, of GS-4224 in blood and tumor biopsy samples
• To explore biomarkers that may predict activity or response to GS-4224, including genetic markers
|
|
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study. Additional indication-specific inclusion criteria for 1000 mg BID Dose Escalation Cohort and Phase 2 are provided in Appendix 3.
1. Male or female ≥ 18 years of age.
2. Dose Escalation Cohorts: Histologically or cytologically confirmed advanced malignant solid tumor that is refractory to or intolerant of all standard therapy or for which no standard therapy is available.
3. Dose Expansion and 1000 mg BID Dose Escalation Cohorts: Subjects must have available sufficient and adequate formalin fixed tumor sample preferably from a biopsy of a tumor lesion obtained either at the time of or after the diagnosis of advanced disease has been made and from a site not previously irradiated. Alternatively, subjects must agree to have a biopsy taken prior to entering the study to provide adequate tissue.
For the 1000 mg BID dose escalation cohort, subjects with melanoma, Merkel cell, MSI-H cancers, and cHL are not required to have archival or fresh biopsy tissue.
4. Dose Escalation Biopsy Substudy and 1000 mg BID Dose Escalation Cohorts: Documented PD-L1 expression in the tumor (TPS ≥10% or CPS ≥ 10). See Appendix 3 for the PD-L1 expression requirement for specific tumor types.
a) In the 1000 mg BID cohort, PD-L1 expression will not be required for Merkel cell, melanoma, MSI-H cancers, and cHL.
5. All persisting toxic effects of any prior antitumor therapy resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 Grade ≤ 1 or baseline before the first dose of study drug (with the exception of alopecia [Grade 1 or 2 permitted] and neurotoxicity [Grade 1 or 2 permitted]).
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
7. Life expectancy of ≥ 3 months, in the opinion of the investigator.
8. Adequate organ function defined as follows:
a) Hematologic: Platelets ≥ 100 109/L ( ≥60 109/L in subjects with HCC); Hemoglobin ≥ 9.0 g/dL; ANC ≥ 1.5 109/L (with without blood transfusion, platelet transfusion, or growth factors within previous 7 days of the hematologic laboratory values obtained at screening visit).
b) Hepatic: AST / ALT ≤ 2.5 upper limit of normal (ULN) (if liver metastases are present, ≤ 5 ULN); Total or conjugated bilirubin ≤ 1.5 ULN.
c) Renal: Creatinine clearance (CLcr) ≥ 45 mL/min as calculated by the Cockcroft Gault method.
9. Coagulation: Subjects on full-dose oral anticoagulation, except warfarin, which is an excluded medication, must be on a stable dose (minimum duration 14 days). Subjects on low molecular weight heparin will be allowed.
10. Negative serum pregnancy test for female subjects.
11. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 5.
12. Females who are nursing must agree to discontinue nursing before the first dose of GS-4224.
13. Able and willing to provide written informed consent to participate in the study.
14. Patients with history of human immunodeficiency virus (HIV) infection should have a CD4+ T-cell count ≥ 350 cells/µL at screening.
15. Patients with serological evidence of chronic hepatitis B virus infection (HBV) should have HBV viral load below the limit of quantification at screening.
16. Patients with serological evidence of hepatitis C virus infection (HCV) should have completed curative antiviral treatment and have HCV viral load below the limit of quantification at screening.
|
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. Additional indication-specific exclusion criteria for 1000 mg BID Dose Escalation Cohort and Phase 2 are provided in Appendix 3.
1) History or evidence of clinically significant disorder, condition, or disease that, in the opinion of the investigator or medical monitor would pose a risk to subject safety or interfere with the study evaluations, procedures, or completion.
2) Dose Escalation Cohorts: History of ≥ Grade 3 AEs during prior treatment with an immune checkpoint inhibitor, or history of discontinuation of treatment with an immune checkpoint inhibitor due to AEs.
3) Dose Escalation 1000 mg BID and Dose Expansion Cohorts: Prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies).
4) History of autoimmune disease (for example, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis).
5) Positive serum pregnancy test (Appendix 5).
6) Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging brain metastases and if taking corticosteroids, are on stable or decreasing doses for at least 7 days from first dose of study drug.
7) Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, active or chronic bleeding event within 28 days prior to first dose of study drug, or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician.
8) Myocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of first dose of study drug.
9) Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (i.e., larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy) within 28 days of the first dose of study drug.
10) Impairment of GI function or GI disease that may significantly alter the absorption of GS-4224, including any unresolved nausea, vomiting, or diarrhea that is Common Terminology Criteria for Adverse Events (CTCAE) Grade > 1.
11) Symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions (including thora- or paracentesis) is eligible.
12) Minor surgical procedure(s) within 7 days of enrollment, or not yet recovered from prior surgery (placement of central venous access device, fine needle aspiration, or endoscopic biliary stent ≥ 1 day before enrollment is acceptable).
13) Prior systemic radiation therapy completed within 4 weeks of the first dose of study drug, prior local radiation therapy completed within 2 weeks of Cycle 1 Day 1 (C1D1), or radiopharmaceuticals (strontium, samarium) within 8 weeks of C1D1.
14) Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy) within 21 days or 5 half-lives, whichever is longer, of study drug dosing (6 weeks for nitrosoureas, mitomycin C, or molecular agents with t1/2 > 10 days); concurrent use of hormone therapy for prostate cancer is permitted.
15) History of long QT syndrome or additional risk factors for Torsades de Pointes or whose corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged (> 480 ms).
16) Use of concomitant medications that prolong QT/QTc interval at screening.
17) Clinically significant bleeding within 28 days of the first dose of study drug.
18) Known hypersensitivity to study drug, the metabolites or formulation excipients.
19) Use of any prohibited concomitant medications as described in Section 5.5 and any investigational agent within 2 weeks of study treatment initiation.
20) Breastfeeding female.
21) Received live virus vaccination within 30 days of first dose of study treatment. Seasonal flu vaccines that do not contain live virus are permitted.
22) History of hematologic stem cell transplant or solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints of this study are:
Phase 1b Dose Escalation
Incidence of dose limiting toxicity (DLT) as defined in Section 3.2 of the protocol. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The study primary analysis will be conducted when all enrolled subjects have discontinued the study or have been on treatment for at least 48 weeks and completed response assessment of Week 48.
Prior to the final analysis, interim analyses may be conducted, and the analyses may be submitted to regulatory agencies to seek guidance for the overall clinical development program. |
|
| E.5.2 | Secondary end point(s) |
Phase 1b Dose Escalation
PK parameters (Tlast, Tmax, Cmax, Ctrough, AUClast, AUCtau and t1/2, as applicable) for GS-4224 in
subjects with advanced solid tumors.
Phase 2 Dose Expansion
Incidence of Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs) in Cohort B1 subjects with advanced solid tumors
Incidence of Grade ≥ 3 Treatment-Emergent laboratory abnormalities in Cohort B1 subjects with advanced solid tumors |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The study primary analysis will be conducted when all enrolled subjects have discontinued the study or have been on treatment for at least 48 weeks and completed response assessment of Week 48.
Prior to the final analysis, interim analyses may be conducted, and the analyses may be submitted to regulatory agencies to seek guidance for the overall clinical development program.
The evaluation of the secondary end point is the same as the primary end point. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| New Zealand |
| Turkey |
| United States |
| Poland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study will be defined when the last subject reaches the last scheduled follow-up timepoint, is lost to follow-up, withdraws from the study, dies, or the time at which the Sponsor
closes the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
