Clinical trial NCT04990739: Study of MTB-9655, an Inhibitor of ACSS2, in Patients With Advanced Solid Tumors
Official title: A Phase 1 Open Label, Multicenter Study of MTB-9655, an Inhibitor of ACSS2, in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: metastatic
ACSS2 inhibitor
Lead sponsor: MetaboMed Inc
Sponsor class: OTHER
First posted: 2021-08-04
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Initial dose escalation will use an accelerated titration scheme followed by a 3+3 dose escalation design.
Primary purpose: TREATMENT

Brief summary: MetaboMed is developing MTB-9655, an orally bioavailable, first-in-class small molecule inhibitor of the human Acetyl coenzyme A (Acyl-CoA) synthetase short chain family member 2 (ACSS2) enzyme, as a potential treatment for patients with cancer.

This study is a Phase 1,First-in-Human (FIH), open-label dose-escalation study of MTB-9655 given daily as a single oral (PO) agent. Up to 30 patients with locally advanced, unresectable and/or metastatic solid tumor(s) are expected to be enrolled in the dose-escalation portion (Part A). The study will be conducted at 1 to 2 sites in the United States and Israel.

Detailed description: This Phase 1 First-in-Human (FIH) study is to initiate clinical development of MTB-9655 in patients with advanced solid tumors who have failed or refused standard treatment, or who have a tumor for which no therapy of proven efficacy exists. This study of MTB-9655 may consist of 2 parts: a dose-escalation part to establish a safe and tolerable dose of MTB-9655 in patients with advanced or metastatic solid tumors for which no standard therapy is available or standard therapy has failed (Part A), and a dose expansion phase (Part B) which may be initiated at the Sponsor's discretion after the maximum tolerated dose (MTD) (or recommended Phase 2 dose \[RP2D\]) has been determined in the dose-escalation (Part A), and with approval of an amendment to the protocol. This study will be the basis for future studies. The study will identify the safety and tolerability of MTB-9655 when administered on a continuous dosing schedule (given by mouth on a 21-day schedule).

Eligibility criteria: Inclusion Criteria:

1. Signed written informed consent.
2. Patient is at least 18 years-of-age at the time of signature of the informed consent form (ICF).
3. Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
4. Patient must have a confirmed diagnosis of locally advanced, unresectable and/or metastatic solid tumor(s), have failed standard treatment, or refuse standard treatment, or have a tumor for which no therapy of proven efficacy exists, or a tumor that is not amenable to standard therapies.
5. Patient has measurable disease on imaging based or non-measurable disease.
6. Patient will be requested to provide a fresh pre-treatment biopsy specimen, otherwise they are required to provide an archival diagnostic tumor sample that is \<1 year old.
7. Patient has a life expectancy ≥3 months according to the Investigator's judgment.
8. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at screening within 72 hours of first dose of MTB-9655. In addition, WOCBP are required to use two forms of acceptable contraception.
9. Male patients with WOCBP partners must agree to use highly effective contraceptive measures throughout the study starting with screening visit through 120 days after the last dose.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Treatment with any of the following:

   * Any systemic anti-cancer chemotherapy, small molecule, biologic, or hormonal agent from a previous treatment regimen or clinical study within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. At least 10 days must have elapsed between the last dose of such agent and the first dose of study drug.
   * Wide-field radiotherapy administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug.
   * Major surgery(excluding placement of vascular access) within 3 weeks of first dose of study drug.
   * Prior treatment with other drug with the same mechanism of action (directed to ACSS2).
   * Receiving systemic corticosteroid therapy 1 week prior to the first dose of study drug or receiving any other form of systemic immunosuppressive medication for medically significant acute or chronic conditions.
2. Persistent toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade \>1 severity that is related to prior therapy.
3. Central nervous system tumor, metastasis(es), and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period or identified prior to consent.
4. Active infection requiring treatment.
5. Out-of-range laboratory values defined as:

   * Absolute neutrophil count (ANC) \<1.5 × 10\^9/L
   * Hemoglobin \<9 g/dL
   * Platelets \<100 × 10\^9/L)
   * Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) \>2.5 × the upper limit of normal (ULN) or ≥5 × ULN with liver involvement
   * Total bilirubin \>1.5 × ULN
   * Serum creatinine \>1.5 × ULN or creatinine clearance (CrCl≤60mL/min, measured or calculated using the Cockcroft-Gault Method
   * International Normalized Ratio (INR) or prothrombin time (PT) \>1.5 × ULN and activated partial thromboplastin time (aPTT) \>1.5 × ULN (unless patient is receiving anticoagulant therapy)
6. Inability to swallow oral medications or presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of MTB-9655 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, malabsorption syndrome).
7. Any of the following cardiac criteria:

   * Known history of marked prolongation of QT/corrected QT(QT/QTc) interval.
   * Clinically significant cardiovascular disease, including cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure,or serious uncontrolled cardiac arrhythmia requiring medication.
   * History of additional risk factors for Torsade de Pointes (including heart failure, hypokalemia, family history of long QT syndrome, and use of concomitant medications that prolong the QT/QTc interval.
   * Patients with a left ventricular ejection fraction (LVEF) \<50%.
8. History of concomitant malignancy with recurrence \<3 year from enrolment.
9. Expected to require any other form of systemic or localized antineoplastic therapy while on trial.
10. Significant liver cirrhosis defined as Child-Pugh Class B or C.
11. History of hemolytic disorders.
12. Active infection with human immunodeficiency virus (HIV).
13. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
14. Pregnant or breastfeeding.

Primary outcomes:
measure: Part A: Number of participants with dose limiting toxicities (DLTs) from MTB-9655 monotherapy in patients with locally advanced or metastatic solid tumors.
timeFrame: 21 days
measure: Part A: Maximum tolerated dose (MTD) by the number of participants with dose limiting toxicities (DLTs) from MTB-9655 monotherapy
timeFrame: At the end of Cycle 1 (each cycle is 21 days)
measure: Recommended Phase 2 dose (RP2D) of MTB-9655 monotherapy in patients with locally advanced or metastatic solid tumors.
timeFrame: From Cycle 1 Day 1 until up to 30 days post last dose (each cycle is 21 days)
measure: Number of participants with adverse events following administration of MTB-9655
timeFrame: From Cycle 1 Day 1 until up to 30 days post last dose (each cycle is 21 days)
Secondary outcomes:
measure: Pharmacokinetic Analysis single dose : maximum plasma concentration (Cmax) for MTB-9655
timeFrame: 22 days ,from Cycle 0 to Cycle 2 Day1. Each cycle is 21 days.
measure: Pharmacokinetic Analysis (multiple dose): Time to maximum plasma concentration at steady state (tmax ss) for MTB-9655
timeFrame: 22 days -from Cycle 0 to Cycle 2 Day1. Each cycle is 21 days.
measure: Overall response rate in participants receiving MTB-9655
timeFrame: Every 6 weeks from Cycle 1 Day1 for 24 weeks, then every 12 weeks up to 24 months (each cycle is 21 days)
measure: Duration of response based on RECIST 1.1
timeFrame: Every 6 weeks from Cycle 1 Day 1 for 24 weeks, then every 12 weeks until disease progression or death or up to 1 year
measure: Disease control rate based on RECIST 1.1
timeFrame: Every 6 weeks from Cycle 1 Day 1 for 24 weeks, then every 12 weeks until disease progression or death or up to 1 year
measure: Progression free survival based on RECIST 1.1
timeFrame: Every 6 weeks from Cycle 1 Day 1 for 24 weeks, then every 12 weeks until disease progression or death or up to 1 year
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Haifa
country: Israel
facility: Rambam MC
city: Tel Aviv
country: Israel
facility: Sourasky MC
Study officials:
affiliation: SCRI Development Innovations, LLC
name: Meredith McKean, MD
role: STUDY_CHAIR
References: