Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202203779032822 Date of Approval: 16/03/2022
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title GO42144
Official scientific title A PHASE Ia/Ib DOSE-ESCALATION AND DOSE- EXPANSION STUDY EVALUATING THE SAFETY, PHARMACOKINETICS, AND ACTIVITY OF GDC-6036 AS A SINGLE AGENT AND IN COMBINATION WITH OTHER ANTI-CANCER THERAPIES IN PATIENTS WITH ADVANCED OR METASTATIC SOLID TUMORS WITH A KRAS G12C MUTATION
Brief summary describing the background and objectives of the trial The Kirsten rat sarcoma viral oncogene homolog (KRAS) is a central component of the RAS/MAPK signal transduction pathway, an intracellular network of proteins that transmit extracellular growth factor signals to regulate cell proliferation, differentiation, and survival. Mutations in KRAS can result in alterations at several amino acids, including glycine 12 (G12), glycine 13, and glutamine 61, commonly found in solid tumors and associated with tumorigenesis and aggressive tumor growth (Der et al. 1982; Parada et al. 1982; Santos et al. 1982; Taparowsky et al. 1982; Capon et al. 1983). Oncogenic KRAS mutations that result in the change from G12 to cysteine (G12C) are prevalent in non-small cell lung cancer (NSCLC) (~12%), colorectal cancer (CRC) (~4%), and other tumor types (≤ 4%)(Bailey et al. 2016; Campbell et al. 2016; Giannakis et al. 2016; Hartmaier et al. 2017; Jordan et al. 2017). The available nonclinical data for GDC-6036, together with the early clinical data from other covalent KRAS G12C inhibitors, support the proposed evaluation of GDC-6036 as a single agent in this study. Specific therapies aimed at KRAS G12Cpositive cancer may provide more tolerable and effective treatment options for patients with advanced stage cancers that harbor KRAS G12C. Based on the nonclinical data available for GDC-6036 and on clinical data from other covalent KRAS G12C inhibitors, the Sponsor has assessed the benefit-risk profile of GDC-6036 as a single agent to be appropriate for initiating this first-in-human clinical study.The mechanistic rationale along with data from in vitro and in vivo combination studies (refer to the GDC-6036 Investigator's Brochure) have guided the selection of anti-cancer therapies to be evaluated in combination with GDC-6036. Combination arms of this study will evaluate the safety, tolerability, PK and PD effects, immunogenicity (when applicable), and preliminary anti-tumor activity of GDC-6036 in combination with other anti-cancer therapies.
Type of trial CCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Cancer
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/08/2022
Actual trial start date
Anticipated date of last follow up 29/11/2024
Actual Last follow-up date
Anticipated target sample size (number of participants) 10
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Non-randomised Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Single Agent GDC6036 400mg - once a day 21 days Cycle During the dose-escalation stage, patients will be evaluated for DLTs at escalating dose levels to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD, if the MTD was not identified) for GDC-6036 as a single agent and in combination with other anti-cancer therapies 5 Uncontrolled
Experimental Group dose expansion stage atezolizumab 1200 mg IV on Day 1 of 21-day cycles (Arm B); cetuximab as an initial dose of 400 mg/m2 IV followed by 250 mg/m2 IV weekly in 21-day cycles (Arm C); bevacizumab 15 mg/kg IV on Day 1 of 21-day cycles (Arm D); and erlotinib 150 mg PO QD in 21-day cycles (Arm E). 21 days cycles The starting dose of GDC-6036 will be 50 mg, administered PO QD in the first cohort (Stage I Arm A). The dose will be increased by up to 100% of the preceding dose level for each successive cohort, until a safety threshold is observed. For single-patient dose-escalation cohorts, the safety threshold is defined as a DLT during the DLT assessment window. For 3+3 dose-escalation cohorts, the safety threshold is defined as a DLT in 1 patient or a study drug–related Grade  2 adverse event (excluding laboratory abnormalities that are asymptomatic and considered by the investigator not to be clinically significant) occurring in at least 2 patients and at least 50% of patients during the DLT assessment window in a given cohort under evaluation for DLT. Once the safety threshold has been met in a given cohort, the dose will be increased by up to 50% of the preceding dose level for each successive cohort. 5
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
 Signed Informed Consent Form  Age ≥18 years at time of signing Informed Consent Form  Ability to comply with the study protocol, in the investigator’s judgment  Evaluable or measurable disease per RECIST v1.1  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1  Life expectancy of ≥12 weeks  Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following:  Absolute neutrophil count ≥1200/µL  Hemoglobin ≥9 g/dL  Platelet count ≥100,000/µL  Total bilirubin ≤1.5 x ULN  Serum albumin ≥2.5 g/dL  AST and ALT≤2.5 x ULN with the following exception: Patients with documented liver metastases may have AST and/or ALT ≤5.0 x ULN.  For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below: Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year and must refrain from donating eggs during the treatment period and after the final dose of study treatment for at least:  6 months for GDC-6036  5 months for atezolizumab (Arm B)  2 months for cetuximab (Arm C)  6 months for bevacizumab (Arm D)  2 weeks for erlotinib (Arm E)  6 months for GDC-1971 (Arm F)  Inability or unwillingness to swallow pills  Inability to comply with study and follow-up procedures  Malabsorption syndrome or other condition that would interfere with enteral absorption  Known and untreated, or active central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: − Measurable or evaluable disease outside the CNS − No history of intracranial hemorrhage or spinal cord hemorrhage − No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for  2 weeks prior to enrollment and no ongoing symptoms attributed to CNS metastases − No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to Day 1 of Cycle 1 − No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study − Note: Patients with new asymptomatic CNS metastases detected at screening are eligible for the study after receiving radiotherapy and/or surgery. Following treatment, these patients may be eligible without the need to repeat the additional brain scan, if all other criteria are met.  Leptomeningeal disease or carcinomatous meningitis  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable and symptomatically improved, and after discussion with the Medical Monitor. Adult: 19 Year-44 Year 18 Year(s) 80 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 07/04/2022 Aga Khan University Nairobi Institutional Ethics Review Committee
Ethics Committee Address
Street address City Postal code Country
3rd Parklands Avenue, off Limuru Road Nairobi 00100 Kenya
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome The safety objective for this study is to evaluate the safety of GDC-6036 as a single agent and in combination with other anti-cancer therapies on the basis of the following endpoints:  Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)  Incidence and nature of dose-limiting toxicities (DLTs)  Change from baseline in targeted vital signs  Change from baseline in targeted clinical laboratory test results  Change from baseline in targeted ECG parameters 1 year
Secondary Outcome The pharmacokinetic (PK) objectives for this study are to characterize the PK profile of GDC-6036 when administered as a single agent and in combination with other anti-cancer therapies and to characterize the PK profile of these anti-cancer therapies when administered in combination with GDC-6036, on the basis of the following endpoints:  Plasma concentrations of GDC-6036, erlotinib, and GDC-1971 at specified timepoints  Serum concentrations of atezolizumab, cetuximab, and bevacizumab at specified timepoints The exploratory PK objectives for this study are as follows:  To evaluate potential relationships between drug exposure and the safety and activity of GDC-6036 as a single agent and in combination with other anti-cancer therapies  To evaluate the exposure of potential circulating metabolite of GDC-6036 following a single or repeat oral dose(s) of GDC-6036 as a single agent or in combination with other anti-cancer therapies  To assess ex vivo plasma protein binding of GDC-6036 and its impact on pharmacokinetics (Arm A only)  To evaluate the effect of GDC-6036 on plasma levels of 4b-hydroxy cholesterol, an endogenous biomarker of CYP3A4 induction (Arm A only)  To evaluate the effect of a standard meal taken within 30 minutes of a GDC-6036 oral dose on the pharmacokinetics of GDC-6036 (Arm A only)  To assess potential relationships between drug exposures and the safety and activity of GDC-1971 in combination with GDC-6036 1 year
Secondary Outcome The exploratory immunogenicity objective for this study is to evaluate the immune response to study biotherapeutics on the basis of the following endpoints:  Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs after initiation of study treatment  Evaluation of safety, efficacy, PD, and PK endpoints by ADA status 1 year
Secondary Outcome The activity objective for this study is to make a preliminary assessment of the activity of GDC-6036 as a single agent and in combination with other anti-cancer therapies on the basis of the following endpoints:  Objective response rate (ORR), defined as the proportion of patients with a complete response (CR) or PR on two consecutive occasions  4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)  Duration of response (DOR), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause during the study (whichever occurs first), as determined by the investigator according to RECIST v1.1  Progression-free survival (PFS), defined as the time from first treatment at Cycle 1 Day 1 to the first occurrence of disease progression or death from any cause during the study (whichever occurs first), as determined by the investigator according to RECIST v1.1 1 year
Secondary Outcome The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that are potentially predictive of response to GDC-6036 as a single agent or in combination with other anti-cancer therapies (i.e., predictive biomarkers), early surrogates of activity, associated with progression to a more severe disease state (i.e., prognostic biomarkers), associated with intrinsic or acquired resistance to KRAS G12C inhibitors (e.g., GDC-6036), associated with susceptibility to developing adverse events or can lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence of GDC-6036 activity as a single agent or in combination with other anti-cancer therapies (i.e., pharmacodynamic [PD] biomarkers), or can increase the knowledge and understanding of disease biology and drug safety. Corresponding biomarker endpoints include the following:  Relationship between exploratory biomarkers in blood, plasma, and tumor tissue (listed in Section 4.5.6) and safety, PK, activity, or other biomarker endpoints 1 year
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Aga Khan University Hospital Nairobi 3rd Parklands Avenue, off Limuru Road Nairobi 00100 Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
Genentech Incl 1, DNA Way, South San Francisco South San Francisco United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Genentech Inc. 1, DNA Way, South San Francisco South San Francisco 1,DNA Way United States of America Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Mansoor Saleh mansoor.saleh@aku.edu +254709931097 3rd Parklands Avenue, off Limuru Road
City Postal code Country Position/Affiliation
Nairobi 00100 Kenya Principal investigator
Role Name Email Phone Street address
Scientific Enquiries Mansoor Saleh mansoor.saleh@aku.edu +254709931097 3rd Parklands Avenue, off Limuru Road,
City Postal code Country Position/Affiliation
Nairobi 00100 Kenya Study Doctor
Role Name Email Phone Street address
Public Enquiries Asim Shaikh asim.jamal@aku.edu +254725111835 3rd Parklands Avenue, off Limuru Road
City Postal code Country Position/Affiliation
Nairobi 00100 Kenya Sub investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Immediately following publication, no end date Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol When the clinical study report is final To be confirmed
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information