| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Recurrent KRAS-Mutant (KRAS-MT) and BRAF-Mutant (BRAF-MT) Non-Small Cell Lung Cancer (NSCLC)
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| E.1.1.1 | Medical condition in easily understood language |
| Specific type of lung cancer called Non-Small Cell Lung Cancer (NSCLC) |
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| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
Part A:
KRAS-G12V NSCLC
To determine the optimal regimen, either VS-6766
monotherapy or VS-6766 in combination
with defactinib, for subsequent evaluation for
efficacy in the expansion phase (Part B)
BRAF-MT NSCLC (V600E and non-V600E)
To evaluate the initial efficacy of VS-6766 in combination with defactinib
Part B:
KRAS-G12V NSCLC
To determine the efficacy of the optimal regimen identified from Part A
BRAF-MT NSCLC (V600E and non-V600E)
To determine the efficacy of VS-6766 in combination with defactinib
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|
| E.2.2 | Secondary objectives of the trial |
To characterize the safety and toxicity profile of VS-6766 as a
monotherapy and in combination with defactinib in KRAS-MT NSCLC and
in BRAF-MT NSCLC
To characterize the pharmacokinetics (PK) of VS-6766,
defactinib, and relevant metabolites
Part A:
To evaluate additional efficacy parameters for
VS-6766 monotherapy and in combination with
defactinib
Part B:
KRAS-G12V NSCLC
To evaluate additional efficacy parameters for the optimal regimen
identified in Part A
BRAF-MT NSCLC (V600E and non-V600E)
To evaluate additional efficacy parameters of VS-6766 in combination
with defactinib
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients ≥ 18 years of age.
2. Histologic or cytologic evidence of NSCLC without histological evidence of a small cell component that is either metastatic (Stage 4) or locally advanced (Stage 3B-C) and unresectable (IASLC 8th edition). The Sponsor’s Medical Monitor must review the
pathology report prior to start of treatment.
3. Patients must have a known KRAS or BRAF mutation determined using a validated next-generation
sequencing (NGS) and/or polymerase chain reaction (PCR) testing method prior to enrollment. Adequate material (as defined in the lab manual) must be available prior to first dose of study intervention to be used for central confirmation of KRAS mutation status. Central confirmation does not need to be completed prior to enrollment.
a. In Part A of the study, patients must have one of the following: a
KRAS-G12V mutation, any other KRAS mutation (KRAS-other, including
KRAS-G12C), a BRAF V600E mutation, or any other BRAF mutation (BRAF
non-V600E).
b. In Part B of the study in patients with KRAS-MT NSCLC, patients must
have either a KRAS-G12V mutation or another specific type(s) of KRAS
mutation(s) (KRAS-selected), to be determined at the end of Part A.
c. In Part B of the study in patients with BRAF-MT NSCLC, patients must
have either a BRAF-V600E mutation, or any other BRAF mutation (BRAF
non-V600E).
4. The patients has received appropriate therapy for an activating
mutation of BRAF, the epidermal growth factor receptor (EGFR),
anaplastic lymphoma kinase (ALK), or other activating mutation in which
a therapeutic has been approved.
5. The patient has received appropriate platinum-based therapy for a non-activating mutation, such as those mentioned in inclusion criterion #3, and has received appropriate treatment with a monoclonal antibody to PD-1 or PD-L1 unless contraindicated.
6. The patient must have received appropriate treatment with at least one prior systemic regimen, but no more than 2 prior regimens, for Stage 3B-C or 4 NSCLC. Patients with Stage 3B-C disease must have received prior radiotherapy or chemoradiotherapy.
7. The patient may have previously received adjuvant chemotherapy for earlier stage disease. Adjuvant chemotherapy in early stages will not count as a prior regimen unless disease progression occurred during or within 3 months following adjuvant therapy.
8. Measurable disease according to RECIST 1.1. All radiology studies must be performed within 28 days prior to start of study-directed therapy.
9. An Eastern Oncology Cooperative Group (ECOG) performance status ≤ 1.
10. Must have adequate organ function defined by the following laboratory parameters:
a. Adequate hematologic function including: hemoglobin (Hb) ≥ 9.0 g/dL; platelets ≥100,000/mm3 ; and absolute neutrophil count (ANC) ≥ 1500/mm3 ) If a red blood cell transfusion support has been administered the Hb must remain stable and ≥ 9.0 g/dL for at least 1 week prior to first dose of study intervention.
b. Adequate hepatic function: (i) total bilirubin ≤ 1.5 × upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 μmole/L) upon discussion with Medical Monitor. (ii) alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) ≤ 2.5 × ULN or < 5 x ULN in patients with liver metastases).
c. Adequate renal function with a creatinine clearance rate of ≥ 50
mL/min as calculated by the Cockcroft-Gault formula) or serum
creatinine of ≤ 1.5 x ULN.
d. International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation.
e. Albumin ≥ 3.0 g/dL (451 μmole/L).
f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
g. Adequate cardiac function with left ventricular ejection fraction ≥ 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
11. Baseline corrected QT interval (QTc) < 460 ms for women and ≤450 ms for men (average of triplicate readings) Common Terminology Criteria for Adverse Events (CTCAE Grade 1) using Fredericia’s QT correction formula. NOTE: This criterion does not apply to patients with a right or left bundle branch block.
12. Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2. Patients with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the Sponsor.
13. Male and female patients with reproductive potential agree to use highly effective method of contraceptive (per Clinical Trial Facilitation Group [CFTG] recommendations in Section 11.4) during the trial and for 3 months following the last dose of study drug interventions for male patients, and 1 month following the last dose of study interventions for female patients. |
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| E.4 | Principal exclusion criteria |
1. Systemic anti-cancer therapy within 4 weeks of the first dose of study intervention.
2. History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.
3. Major surgery within 4 weeks (excluding placement of vascular
access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study intervention.
4. Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low- molecular weight heparin or direct oral anticoagulants (DOAC)s.
5. History of treatment with a direct and specific inhibitor of BRAF or
MEK, except for treatment of BRAF-V600E-mutant NSCLC.
6. History of treatment with a direct and specific inhibitor of KRAS
7. Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug
interactions with study interventions within 14 days prior to the first
dose of study intervention(s) and during the course of the therapy:
a. Strong CYP3A4 inhibitors or inducers, due to potential drug-drug
interactions with both VS-6766 and defactinib. See Table 20 and Table 21 for representative lists of CYP3A4 inhibitors and inducers.
b. Strong CYP2C9 inhibitors or inducers, due to potential drug-drug
interactions with defactinib. Not applicable if and when patients
randomized to VS-6766 monotherapy See Table 20 and Table 21 for
representative lists of CYP2C9 inhibitors and inducers.
c. P-glycoprotein (P-gp) inhibitors or inducers, due to potential drugdrug interactions with defactinib. Not applicable if and when patients randomized to VS-6766 monotherapy. See Table 23 for representative lists of P-gp inhibitors and inducers.
8. Symptomatic brain metastases requiring steroids or other local
interventions. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior
to study entry, have discontinued corticosteroid treatment for these
metastases for at least 2 weeks prior to first dose of study intervention, and are neurologically stable, with no evidence of interim progression. Patients with new asymptomatic CNS metastases detected during the screening period must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may then be eligible if all other criteria are met.
9. Known severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection clinical symptoms ≤28 days prior to first dose of study
intervention.
10. Known hepatitis B, hepatitis C or human immunodeficiency virus
infection that is active and/or requires therapy.
11. Active skin disorder that has required systemic therapy within the
past 1 year.
12. History of rhabdomyolysis.
13. Concurrent ocular disorders:
a. Patients with history of glaucoma, history of retinal vein occlusion
(RVO),predisposing factors for RVO, including uncontrolled
hypertension, uncontrolled diabetes.
b. Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO.
c. Patients with a history of corneal erosion (instability of corneal
epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions.
14. Concurrent congestive heart failure, prior history of class III/ IV
cardiac disease (New York Heart Association [NYHA]), myocardial
infarction within the last 6 months, unstable arrhythmias, unstable
angina or severe obstructive pulmonary disease.
15. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
16. Patients with a history of hypersensitivity to any of the active (VS-
6766, defactinib) or inactive (hydroxypropylmethylcellulose, mannitol,
magnesium stearate) ingredients of the investigational products.
17. Female patients who are pregnant or breastfeeding.
18. Any other medical condition (e.g. cardiac, gastrointestinal,
pulmonary, psychiatric, neurological, genetic, etc.) that in the opinion of the investigator would places the patient at unacceptably high risk for toxicity.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A:
Confirmed overall response rate (ORR; partial response [PR] + complete response [CR] defined according to Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1] as assessed by the Blinded Independent Radiology Review Committee (BIRC)
Part B:
Confirmed ORR defined according to RECIST
1.1 as assessed by the BIRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Adverse events (AEs), serious AEs (SAEs), vital
signs, physical examinations, clinical laboratory
values, and tolerability (dose interruptions/reductions)
Duration of response (DOR)
ORR as assessed by the Investigator
Disease control rate (DCR), defined as
CR+PR+ stable disease (SD)
Progression free survival (PFS), defined as the
time from first dose of study intervention to the
first documentation of progressive disease (PD) or death from any cause
Overall survival (OS)
PK parameters derived from blood concentrations
of VS-6766, defactinib, and relevant metabolites |
|
| E.5.2.1 | Timepoint(s) of evaluation of this 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Part A: a “Go Forward” strategy with accrual based on 3 treatment arms and Part B Expansion Phase |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| VS-6766 In Combination with Defactinib |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| United States |
| France |
| Spain |
| Germany |
| Italy |
|
| 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
|
A patient is considered to have completed the study if he/she has completed the last scheduled procedure shown in the Schedule of Activities (SoA) , including the Survival Follow-up of up to 1 year after discontinuation of study therapy.
The end of the study is defined as the date of the last scheduled procedure shown in the SoA for the last patient in the study.
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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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