Clinical trial NCT04665206: Study to Evaluate VT3989 in Patients with Metastatic Solid Tumors
Official title: Phase 1, Multi-Center, Open-Label Study of VT3989, Alone or in Combination, in Patients with Refractory Locally Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Solid Tumor, Adult
Mesothelioma
NSCLC
Lead sponsor: Vivace Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2020-12-11
Enrollment: 336
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part 1 dose escalation: 3 + 3 design Part 2 dose expansion: up to 6 cohorts Part 3 combination: 2 cohorts
Primary purpose: TREATMENT

Brief summary: This is an open-label, dose escalation and expansion study to evaluate the safety, tolerability, PK, and biological activity of VT3989 administered, alone or in combination, once daily in 3- or 4-week cycles in patients with mesothelioma and/or metastatic solid tumors that are resistant or refractory to standard therapy or for which no effective standard therapy is available.

Detailed description: Dose escalation (Part 1) will employ a traditional 3 + 3 design to assess safety of VT3989 in patients with refractory metastatic solid tumors or mesothelioma. The 3 + 3 design will be implemented until the MTD or recommended phase 2 dose(s) and schedule(s) are determined. The MTD is defined as the highest dose level at which \< 33% of patients experience a dose limiting toxicity (DLT) during the first cycle of the study (Cycle 1).

Dose Expansion (Part 2) will further evaluate the safety and assess preliminary antitumor activity at the recommended phase 2 dose(s) and schedule(s) with up to 6 cohorts. Expansion cohorts 1 and 2 will enroll patients with mesothelioma of any site origin with or without NF2 mutations. Expansion cohort 3 will enroll non-pleural mesothelioma patients. Expansion cohort 4 will enroll solid tumor patients with clearly inactivating NF2 mutations/alterations or YAP/TAZ gene rearrangements. Cohort 5 will enroll pleural mesothelioma patients.

Combination part (Part 3) includes two cohorts. Cohort A will enroll mesothelioma patients who will receive VT3989 in combination with immunotherapy (nivolumab plus ipilimumab). Cohort B will enroll NSCLC patients whose tumors have exon 19 deletion or exon 21 L858R mutation and will receive VT3989 in combination with targeted therapy (Osimertinib).

Eligibility criteria: Inclusion Criteria:

* Part 1: pathologically diagnosed metastatic solid tumor or mesothelioma that has progressed on or after all approved therapies of known clinical benefit except if the patient refuses or is not a candidate for such therapy;
* Part 2 Expansion Cohorts 1 and 2: in mesothelioma cohorts, pathologically diagnosed advanced malignant mesothelioma with or without NF2 mutations, that has progressed on or after all approved therapies of known clinical benefit except if the patient refuses or is not a candidate for such therapy.
* Part 2 Expansion Cohort 3: non-pleural mesothelioma patients with epithelioid histology, relapsed from or refractory to prior platinum-based chemotherapy and immunotherapy.
* Part 2 Expansion Cohort 4: in the solid tumor cohort, pathologically diagnosed metastatic or locally advanced solid tumor with clearly inactivating NF2 mutations/alterations or YAP/TAZ gene rearrangements, which have progressed on or after approved therapies of known clinical benefit except if the patient refuses or is not a candidate for such therapy.
* Part 2 Expansion Cohort 5: pathologically diagnosed advanced malignant pleural mesothelioma with epithelioid histology, that has progressed on or after licensed immunotherapy, chemotherapy or combined chemoimmunotherapy except if the patient refuses or is not a candidate for such therapy.
* Part 3 Combination Cohort A: pathologically diagnosed, metastatic or unresectable malignant mesothelioma including both pleural and non-pleural) patients who have not received systemic therapy.
* Part 3 Combination Cohort B: pathologically diagnosed incurable locally advanced (inoperable or recurrent), or metastatic NSCLC with exon 19 deletions or exon 21 L858R mutations, with or without prior treatment with Osimertinib.
* Part 1: evaluable or measurable disease per RECIST v1.1 or mRECIST
* Part 2 and 3: measurable disease per RECIST v1.1 for non-pleural mesothelioma or other solid tumors or modified RECIST v1.1 for malignant pleural mesothelioma. mRECIST may be used for pleural extension of non-pleural mesothelioma or for mixed pleural and peritoneal (or other) mesothelioma.
* ECOG: 0-1
* Adequate organ functions, including the liver, kidneys, and hematopoietic system

Exclusion Criteria:

* Active brain metastases or primary CNS (central nervous system) tumors.
* History of leptomeningeal metastases
* Active or chronic, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
* Known HIV positive or active Hepatitis B or Hepatitis C
* Clinically significant cardiovascular disease
* Corrected QT (QTcF) interval \> 470 msec (using Fridericia's correction formula); except for Part 2 Expansion Cohort 3, the QTcF interval criteria is \> 450 msec)
* Additional active malignancy that may confound the assessment of the study endpoints
* Women who are pregnant or breastfeeding
* Prior treatment with TEAD inhibitor, except for EHE patients

Primary outcomes:
measure: Occurrence of Dose Limiting Toxicity
timeFrame: over the first 21 days of dosing
measure: Occurrence of General Toxicity
timeFrame: through study completion, an average of 30 months
Secondary outcomes:
measure: Tumor Response
timeFrame: through study completion, an average of 30 months
measure: Pharmacokinetic Evaluation - Cmax
timeFrame: for first 6 cycles
measure: Pharmacokinetic Evaluation - Tmax
timeFrame: for first 6 cycles
measure: Pharmacokinetic Evaluation - Half-life
timeFrame: for first 6 cycles
measure: Overall survival (Part 2, expansion cohort 3 only)
timeFrame: Through study completion, an average of 30 months
measure: Progression free survival (Part 2, expansion cohort 3 only)
timeFrame: Through study completion, an average of 30 months
measure: Quality of life assessment (Part 2, expansion cohort 3 only)
timeFrame: Through study completion, an average of 30 months
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: M Health Fairview University of Minnesota Medical Center
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center-
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCullum Cancer Centre
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research
state: Western Australia
Study officials:
affiliation: Vivace Therapeutics
name: Neelesh Sharma, MD
role: STUDY_DIRECTOR
References: