This study has been transitioned to CTIS with ID 2023-507171-22-00 check the CTIS register for the current data. The purpose of this study is to evaluate the safety, pharmacokinetics, and activity of GDC-6036 combined with other anti-cancer…
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Source
Brief title
Condition
- Other condition
Synonym
Health condition
NON-SMALL CELL LUNG CANCER MET EEN KRAS G12C MUTATION
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Occurrence of adverse events
2. Change from baseline at each visit in targeted safety parameters
Secondary outcome
1. Objective response rate
2. Duration of response
3. Progression free survival
4. Presence, frequency of occurrence, severity, and/or degree of interference
with daily function of symptomatic side effects as assessed
through use of the Patient-Reported Outcomes Common Terminology Criteria for
Adverse Events (PRO*CTCAE)
5. Change from baseline in symptomatic side effects, as assessed through use of
the PRO-CTCAE
6. Proportion of participants reporting "frequent" or "almost constant"
diarrhea during the first three cycles of treatment according to the PRO
CTCAE-criteria
7. Proportion of participants reporting "severe" or "very severe" nausea or
vomiting during the first three cycles of treatment according to the
PRO-CTCAE
8. Frequency of participant's response of the degree they are troubled with
treatment symptoms, as assessed through use of the single-item
European Organisation for Research and Treatment of Cancer (EORTC) Item List 46
(IL46)
9. Plasma concentration of GDC-6036 at specified timepoints
10. Identification of GDC-6036 recommended dose in combination with
pembrolizumab based on the totality of safety, activity, and PK data
Background summary
Lung cancer remains the leading cause of cancer deaths worldwide and is one of
the most common cancers in both men and women. NSCLC is the predominant subtype
of lung cancer, accounting for approximately 85% of all cases. The overall
5-year survival rate for advanced disease is 2%-4%, depending on geographic
location. NSCLC is a heterogeneous disease, and it has become increasingly
important to perform broad predictive molecular biomarker analyses when
determining a treatment approach for patients with advanced or metastatic
disease. The recommendation to test for KRAS mutations is relatively recent.
PD-L1 expression is considered the best available predictive biomarker for
immunotherapy and is also recommended to be tested in all patients with
advanced or metastatic NSCLC. Despite improvements and benefits with PD-L1/PD-1
targeting agents, nearly all patients experience disease progression.
Consequently, new treatments and treatment regimens, including CPI/targeted
therapy combinations, are needed to address this unmet medical need.
GDC-6036 is an oral, covalent, anti-cancer therapeutic agent that selectively
inhibits KRAS G12C.
Study objective
This study has been transitioned to CTIS with ID 2023-507171-22-00 check the CTIS register for the current data.
The purpose of this study is to evaluate the safety, pharmacokinetics, and
activity of GDC-6036 combined with other anti-cancer therapies in patients with
previously untreated, advanced or metastatic non-small cell lung cancer (NSCLC)
that harbors a Kirsten rat sarcoma viral oncogene homolog (KRAS) glycine 12 to
cysteine (G12C) mutation (KRAS G12C*). First-line treatment options for
patients with KRAS G12C* NSCLC include immunotherapy as a single agent or in
combination with chemotherapy. Although a minority of patients achieve
long-term disease control with programmed death*1 (PD-1)/programmed
death*ligand 1 (PD-L1) inhibitor treatment, in general, advanced stage or
metastatic NSCLC remains an incurable disease with limited benefit from the
available standard of care treatments, thus demonstrating an unmet medical need
in this patient population. Novel combinations using a more targeted, biomarker
directed approach may further improve outcomes. The first combination to be
evaluated in the study will be GDC-6036 in combination with pembrolizumab but
other combinations with GDC 6036 may be added to the study through protocol
amendments in line with the overall study rationale. Anticipated future
combinations with GDC-6036 may for example include immunotherapy combined with
another immunotherapy or immunotherapy combined with chemotherapy.
Study design
This is an open-label, multicenter Phase Ib/II study designed to evaluate the
safety, pharmacokinetics, and activity of GDC-6036 in combination with other
anti-cancer therapies in patients with untreated advanced or metastatic NSCLC
that harbors a KRAS G12C mutation. This study is designed with the intention to
include new, additional treatment arms during study conduct and in line with
the overall study rationale (via substantial protocol amendments) to explore
combinations for GDC-6036 with other anti-cancer therapies based on emerging
nonclinical and clinical data with GDC-6036 and other KRAS G12C inhibitors.
Initially, a cohort of GDC 6036 in combination with pembrolizumab (Cohort A)
will be evaluated. Anticipated future combinations with GDC 6036 may for
example include immunotherapy combined with another immunotherapy or
immunotherapy combined with chemotherapy.
Intervention
• GDC-6036: 200 mg or 400 mg orally, once a day, on Days 1-21 of each 21-day
cycle.
The dose of GDC-6036 can be reduced up to two times for management of drug
related toxicities.
• Pembrolizumab: 200 mg IV, every 3 weeks, on Day 1 of each 21-day cycle.
Modification of the pembrolizumab dose, including dose reductions, is not
permitted.
Study burden and risks
The purpose of this study is to assess the safety, pharmacokinetics, and
activity of GDC 6036 in combination with other anti-cancer therapies to address
a significant unmet medical need in patients with previously untreated,
advanced or metastatic NSCLC harboring a KRAS G12C mutation, and who are not
eligible for curative surgery and/or definitive chemoradiotherapy.
It has recently become a recommendation to test for KRAS G12C mutations based
on the emergence of specific targeted treatment options. While there have been
several advances in the treatment of advanced or metastatic NSCLC with targeted
therapies that inhibit specific actionable driver mutations such as EGFR, ALK,
ROS1, and BRAF as an example, mutant KRAS has historically been considered
"undruggable" due to its high affinity for GTP, lack of accessible binding
pockets, and the toxicity associated with non*mutant-specific targeting
approaches.
With the landmark discovery of the switch II pocket, covalent small molecule
inhibitors aimed at targeting KRAS, and specifically the KRAS G12C mutation,
are being evaluated in clinical development. A brief summary of available
clinical data for other KRAS G12C inhibitors in development is provided in
paragraph 2.3 of the protocol, followed by a detailed description of GDC 6036,
the KRAS G12C inhibitor that will be administered in this study.
Based on the considerations described in paragraph 2.3 of the Protocol, and the
planned safety monitoring and management guidance, the proposed treatments are
considered to have an appropriate benefit-risk profile for the population
included in this cohort.
Beneluxlaan 2A
Woerden 3446AA
NL
Beneluxlaan 2A
Woerden 3446AA
NL
Listed location countries
Age
Inclusion criteria
- Histologically or cytologically documented locally advanced unresectable or
metastatic NSCLC that is not eligible for curative surgery and/or definitive
chemoradiotherapy
- No prior systemic treatment for advanced unresectable or metastatic NSCLC
- Confirmation of Biomarker eligibility:
.. Documented history of the KRAS G12C mutation
.. Documented history of PD-L1 tumor cell expression >=1%
- Pre-treatment tumor tissue along with an associated pathology report is
required for all participants enrolled on study. Representative tumor
specimens must be in formalin*fixed, paraffin embedded (FFPE) blocks
(preferred) or 15 unstained, freshly cut, serial slides. Although 15 slides
are required, if only 10 slides are available, the participant may be eligible
for the study following consultation with the Sponsor
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
- Measurable disease, as defined by Response Evaluation Criteria in Solid
Tumors (RECIST) v1.1
Exclusion criteria
- Known concomitant second oncogenic driver with available targeted treatment
- Symptomatic, untreated, or actively progressing central nervous system (CNS)
metastases
- Prior treatment with a KRAS G12C inhibitor
- Known hypersensitivity to any of the components of GDC-6036 or pembrolizumab
- History of malignancy other than NSCLC within 5 years prior to initiation of
study treatment, with the exception of malignancies with a negligible risk of
metastasis or death (e.g., 5-year OS rate more >90%), such as adequately
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized
prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer
- Uncontrolled tumor related pain, pleural effusion, pericardial effusion, or
ascites requiring recurrent drainage procedures, uncontrolled or symptomatic
hypercalcemia
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis,
or evidence of active pneumonitis, active tuberculosis, significant
cardiovascular disease within 3 months prior to initiation of study treatment
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-507171-22-00 |
| EudraCT | EUCTR2022-003048-28-NL |
| Other | IND: 147339, NCT05789082 |
| CCMO | NL83211.041.23 |