Part A1(KIN-2787 Monotherapy Escalation):Determine safety and tolerability of PO administration of Kin-2787 including DLT in participants with BRAFmutation-positive advanced or metastatic solid tumors or melanoma harboring NRAS-mutation. Identify…
ID
Source
Brief title
Condition
- Other condition
- Skin neoplasms malignant and unspecified
Synonym
Health condition
Any unresectable and locally advanced or metastatic solid tumors
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety endpoints include the following:
• Incidence of dose limiting toxicity (DLTs),
• Incidence of treatment-emergent adverse events (TEAEs), treatmentrelated
AEs
• Clinically significant changes in vital signs, physical examinations,
ECGs, and clinical laboratory tests
Efficacy (as assessed by the Investigator) will be measured by the
following:
• Objective response rate (ORR) defined as the rate of partial responses
(PR) plus
complete responses (CR) according to RECIST v1.1
• Disease control rate (DCR)
• Duration of overall response (DOR)
• Duration of stable disease
Secondary outcome
PK parameters of KIN-2787 and KIN-2787 + binimetinib including, but
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not limited to, maximum observed plasma concentration (Cmax), time to
achieve Cmax (tmax), and area under the plasma concentration-time
curve (AUC), including in the fed and fasted states.
Exploratory Endpoints:
• KIN-2787 and KIN-2787 + binimetinib exposure/safety and
exposure/efficacy relationships
• Characterization of potential metabolites of KIN-2787 in plasma and
urine
• Progression-free survival (PFS), and overall survival (OS)
• Biomarker quantification by biochemical and/or genetic analysis of
blood and/or tumor samples including, but not limited to the
pharmacodynamic effect on pERK, DUSP6 RNA and proliferation marker,
Ki-67.
• Changes in ctDNA concentration and mutational profiles
• Potential biomarkers by biochemical and/or genetic analysis of blood
and/or tumor samples
• Population PK analysis
• Objective response evaluation of previously untreated brain
metastases as assessed by Response Assessment in Neuro-Oncology
Brain Metastases (RANO-BM) by the Investigator.
• Patient reported outcomes (Part B only)
• Evaluation of PK of new tablet formulation (US only)
Background summary
Initially, Kinnate began development of KIN-2787 for the treatment of patients
with melanoma and NSCLC subpopulations with tumors harboring Class II or III
BRAF mutations that include specific BRAF point mutations (other than BRAF
V600E), BRAF insertions/deletions (indels), and
BRAF gene fusion events. These patients are not eligible to receive current
BRAF-targeted therapies, typically do not harbor other oncogenic driver genes
for which targeted therapies are available and have few other treatment
options. Additionally, NSCLC patients and melanoma patients with BRAF Class II
and III mutations have poor prognoses, represent cancer indications of high
need, and will be the primary cancer populations enrolled in Study KN-8701.
Patients with advanced or metastatic NSCLC, melanoma, CRC, and thyroid cancer
with BRAF Class I mutations are eligible to receive approved BRAF-targeted
therapies. These RAF inhibitor drugs are often used in combination with a MEK
inhibitor, and together provide significant clinical benefit. However, due to
the frequent emergence of acquired resistance in many of these patients, and
the fact that other solid tumors driven by Class I, II, or III BRAF mutations
are not eligible for approved BRAF-directed therapies, an unmet need persists
to develop next generation BRAF-targeted therapies. Collectively, these
patients will also be evaluated in Study KN-8701.
Study objective
Part A1(KIN-2787 Monotherapy Escalation):Determine safety and tolerability of
PO administration of Kin-2787 including DLT in participants with BRAF
mutation-positive advanced or metastatic solid tumors or melanoma harboring
NRAS-mutation.
Identify MTD and/or appropriate dose for Part B1
Part A2 (KIN-2787+Binimetinib Escalation):Determine safety and tolerability of
PO administration including DLTs in participants with
oncogenic BRAF or NRAS mutation-positive advanced or metastatic solid tumors.
Identify MTD and/or 1or 2 RP2D for further clinical
investigation
PartB1(KIN-2787 Monotherapy Expansion):Assess preliminary evidence of
anti-cancer activity of KIN-2787 in participants with advanced or
metastatic solid cancers that harbor any oncogenic BRAF genomic alteration
PartB2(KIN-2787+Binimetinib Expansion):evaluate preliminary evidence of
anti-cancer activity of KIN-2787 + binimetinib for tumors with NRAS
Q61, G12, and G13 + and oncogenic BRAF Class II mutations for 1 or more RP2D
based on the results of Part A 2.
Study design
The study consists of Part A Dose Escalation and Part B Dose Expansion, both of
which include
assessment of KIN-2787 monotherapy (Parts A1 and B1) and KIN-2787 + binimetinib
combination therapy (Parts A2 and B2).
Part A (Dose Escalation):
Part A1 will evaluate the safety, tolerability, PK, and pharmacodynamics (PD)
of KIN-2787 in
participants with BRAF mutation-positive advanced or metastatic solid tumors
and/or melanoma harboring an NRAS mutation. Part A1 will use an accelerated
titration design (single-participant dose levels) followed by a traditional 3 +
3 dose-escalation scheme to identify the MTD and/or
RP2D of KIN-2787. The MTD is defined as the maximum daily oral dose at which <
33% of participants experience a DLT during the 28-day DLT evaluation period.
KIN-2787 will be administered as an oral dose twice daily (BID) every day for
28 days in 28-day treatment cycles.
The starting dose, Dose Level (DL) 1, will be 50 mg per day (administered as 25
mg BID), and
dose escalation increments will follow a modified Fibonacci sequence. The
planned KIN-2787 dose levels are indicated in the protocol.
An accelerated titration dose escalation design principle will be employed in
which 1 participant per cohort will be evaluated until evidence of biologic
activity is observed. At which time, that cohort will be expanded by 2
participants. This and all subsequent dose level cohorts will
proceed using the 3 + 3 dose escalation design. For purposes of the above
discussion,
either (1) a DLT or (2) at least 1 Grade 2 adverse event (AE) not clearly
attributable to underlying disease or extraneous cause (excluding
Grade 2 Laboratory Investigation AEs deemed non-clinically significant by the
Investigator).
Starting with DL3, the KIN-2787 dose will be escalated using a traditional 3 +
3 study design and will continue until stopping rules are met, or until the MTD
or the dose at which the anticipated maximal pharmacologic activity (informed
by PK and PD biomarkers) is achieved.
With this 3 + 3 design, at least 3 participants will be enrolled into each dose
level from DL3 onwards. If none of the 3 participants in a dose level
experiences a DLT within the DLT period (28 days from the first dose of
KIN-2787 for all dose levels), another 3 participants will be
treated at the next higher dose level. No additional participants will be
treated at a given dose level if 2 or more of the participants in that dose
level develop a DLT in Cycle 1.
For the first 2 participants who receive KIN-2787 at a specified dose level,
there will be at least 24 hours between the first dose of KIN-2787 in the first
and second participants.
Dose escalation will continue until the highest planned dose level is
determined to be safe and tolerable with a minimum of 6 DLT-evaluable
participants at that dose level (i.e., the dose level considered to be the
RP2D), or until MTD is reached. Up to approximately 26 participants will be
required to estimate the MTD and/or the RP2D.
The Dose Review Committee (DRC) consisting of Investigators and Sponsor
representatives will review all available safety, PK, and PD data prior to
initiating enrollment at the next dose level. The DRC will review the safety
and tolerability of each dose level of KIN-2787 monotherapy after participants
at that particular dose level have completed at least 1 full cycle.
Part A will continue until stopping rules are met or until the MTD or the dose
where the anticipated maximal pharmacologic activity (e.g., RP2D) is achieved.
The DRC will also evaluate all available safety data and PK/PD data to
determine the RP2D for Part B.
The effect of food on the PK of KIN-2787 will be evaluated in at least 6
participants during Part A1 at DL3, DL4, and DL5 using a randomized crossover
design.
Participants who are receiving KIN-2787 monotherapy in Part A1 will have the
opportunity to crossover to combination therapy (Part A2) with KN-2787 +
binimetinib if they meet the criteria specified in the protocol.
Part A2 will not be initiated until preliminary proof of mechanism (PPOM)
clinical criteria have been met in the monotherapy dose escalation cohorts. At
the end of each Part A1 dose level cohort, the DRC will determine if the
criteria for PPOM have been met and will recommend if
Part A2 should be initiated.
Part A2 will include participants with pretreated BRAF Class I, BRAF Class II,
BRAF Class III, or NRAS mutated solid tumors. Emerging clinical data will be
used to monitor and update the prioritization for enrollment of each mutation
type throughout the study. For KIN-2787, the
starting dose will be 1 dose level below the dose level that met PPOM criteria
or 1 dose level below the dose level considered safe at the discretion of the
DRC. For binimetinib, the starting dose will be the labeled, approved dose of
45 mg BID. KIN-2787 and binimetinib will be
administered together as an oral dose every day in 28-day treatment cycles.
Dose escalation for the combination dose levels will follow a 3 +3 design.
Combination dose levels may be assessed in parallel. The DRC will recommend
subsequent combination dose levels based on
available safety, tolerability, and PK data from the previous dose levels.
Intra-participant dose escalations and backfill are allowed in Part A at the
discretion of the Investigator and after consultation with the Sponsor. The
backfill dose level(s) for KIN-2787 monotherapy and for KIN-2787 combination
with binimetinib will be the most recent dose(s) that have been cleared by the
DRC and are regarded as safe and tolerable. Intra-participant dose escalation
may only be considered if the participant meets all protocol-specified criteria.
Part B (Dose Expansion):
Part B1 monotherapy dose expansion part of the study can begin once the
KIN-2787 monotherapy MTD and/or RP2D has been determined in Part A1. Part B1
will evaluate the anti-tumor activity of KIN-2787 monotherapy at the RP2D in
the following cohorts:
Cohort 1: Participants with unresectable and locally advanced (American Joint
Committee on Cancer [AJCC] Stage III) or metastatic (AJCC Stage IV) non-small
cell lung cancer (NSCLC) with any BRAF Class II mutation.
Cohort 2: Participants with unresectable and locally advanced (AJCC Stage III)
or metastatic (AJCC Stage IV) NSCLC with any BRAF Class III or other BRAF
non-Class I mutation.
Cohort 3: Participants with unresectable and locally advanced (AJCC Stage III)
or metastatic (AJCC Stage IV) melanoma with any BRAF Class II mutation
Cohort 4: Participants with unresectable and locally advanced (AJCC Stage III)
or metastatic (AJCC Stage IV) melanoma with any BRAF Class III or other BRAF
non-Class I mutation.
Cohort 5: Participants with any unresectable and locally advanced (AJCC Stage
III, or comparable Stage with other staging systems) or metastatic (AJCC Stage
IV) solid tumor (other than NSCLC or melanoma) with any BRAF Class II mutation
Cohort 6: Participants with any unresectable and locally advanced (AJCC Stage
III, or comparable Stage with other staging systems) or metastatic (AJCC Stage
IV) solid tumor (other than NSCLC or melanoma) with any BRAF Class III or other
BRAF non--Class I mutation.
Cohort 7: Participants with any unresectable and locally advanced (AJCC Stage
III, or comparable Stage with other staging systems) or metastatic (AJCC Stage
IV) solid tumor with any BRAF Class I oncogenic mutation.
Enrollment of participants in the Dose Expansion cohorts will occur
concurrently. The eligibility of participants with certain genetic alterations
may be restricted to ensure appropriate genotype representation. In addition,
in Cohorts 5-7, tumor types will be monitored to ensure a broad
representation of various solid tumors.
In the United States (US) only for all Part B1 cohorts, comparison of the PK of
a new KIN-2787 formulation more suited for commercial manufacture will be
evaluated in approximately 6 participants randomized to the 2 formulations in a
1:1 fashion starting at C1D1.
Part B2, combination Dose Expansion part of the study, can begin once the MTD
and/or the RP2D of KIN-2787 + binimetinib have been identified. Part B2 will
evaluate the anti-tumor activity of KIN-2787 in combination with binimetinib
for 2 cohorts: Cohort 1 for participants with
NRAS mutation solid tumors, including melanoma, and Cohort 2 for participants
with BRAF Class II mutation solid tumors. One or more RP2D may be assessed
within each cohort.
Enrollment into the NRAS and BRAF Class II mutation groups may or may not occur
concurrently depending on the evolving clinical data. Participants' tumor
genetic alterations and various tumor types will be monitored to ensure broad
representation within each cohort.
For both Part B1 and Part B2, a Data Monitoring Committee (DMC) will review all
available safety, tolerability, and treatment efficacy for all cohorts
throughout the duration of the study.
The DMC will recommend continuation or termination of any cohort or even the
study based on the evaluation of the results. A Bayesian efficacy modeling will
be used to conduct continuous monitoring assessment on efficacy data to
evaluate futility.
Intervention
See detailed description in section Study design
Study burden and risks
Please refer to section E.9
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Listed location countries
Age
Inclusion criteria
Key inclusion criteria include the following:
General Considerations:
1. Adult participants (>= 18 years of age) with histologically or cytologically
confirmed diagnosis of metastatic or advanced-stage malignancy will be eligible
for this study.
2. Participants with brain metastasis that are asymptomatic and do not require
treatment in the opinion of the investigator.
3. Participants will provide archived tumor tissue specimen (formalinfixed
paraffin-embedded [FFPE] specimen) obtained within the last 5 years (if
available), and will undergo mandatory pre-treatment
tumor biopsy, if medically feasible.
4. A participant's tumor must harbor an oncogenic BRAF Class I, II, or III
mutation or be melanoma with an NRAS Q61, G12, or G13 positive mutation
identified by previous genomic analysis of tumor tissue or ctDNA conducted in a
Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (in
United States
[US]) or in accordance with local regulatory requirements (in other countries).
Study Part Specific Considerations - Part A1:
1. Participants with any type of advanced or metastatic solid tumor with
oncogenic BRAF Class I, Class II or Class III mutations and NRASmut
positive melanoma.
2, Participants must have received prior standard therapy appropriate
for their tumor type and stage of disease, or in the opinion of the
Investigator, would be unlikely to tolerate or derive clinically meaningful
benefit from appropriate standard of care therapy.
3. However, participants may enroll without having been pretreated with
a small molecule BRAF-, MEK-, or MAPK-directed inhibitor therapy if such
treatment has not been approved for that indication.
Study Part Specific Considerations - Part A2:
1. Participants with NRAS Q61, G12, or G13 positive mutated advanced
solid tumors and oncogenic BRAF pretreated Class I, II or III mutated
advanced solid tumors
2. Participants should have previously received an approved BRAF
inhibitor (with or without an approved MEK inhibitor), if authorized and
available unless, in the opinion of the Investigator, the participant would
be unlikely to tolerate or derive clinically meaningful benefit from that
treatment.
Study Part Specific Considerations - Part B1:
1. Participants with unresectable and locally advanced or metastatic
NSCLC, melanoma, or any other unresectable and locally advanced solid
tumor with oncogenic BRAF Class I, II, or III mutations
Study Part Specific Considerations - Part B2:
1. Participants with advanced or metastatic solid cancers harboring the
NRAS Q61, G12, or G13 mutations or any oncogenic BRAF Class II
mutations.
2. Participants must have received prior standard therapy appropriate
for their tumor type and stage of disease, or in the opinion of the
Investigator, would be unlikely to tolerate or derive clinically meaningful
benefit from appropriate standard of care therapy.
Exclusion criteria
Key exclusion criteria include the following:
. Participants may not have any unresolved toxicities from prior antitumor
therapy or significant concomitant diseases.
2. In Part B1 and B2, previous treatment with any approved or in-development
small molecule BRAF-, MEK-, or MAPK-directed inhibitor therapy is excluded.
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 |
|---|---|
| EudraCT | EUCTR2021-005389-16-NL |
| ClinicalTrials.gov | NCT04913285 |
| CCMO | NL79729.031.22 |