Clinical trial NCT03556228: Selective TrkA Inhibitor VMD-928 to Treat TrkA Overexpression Driven Solid Tumors or Lymphoma
Official title: An Open-Label, Multiple-Dose, Dose-Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of VMD-928 in Subjects With Solid Tumors or Lymphoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Head and Neck Carcinoma
Adenoid Cystic Carcinoma
Lung Cancer
Non-Small Cell Lung Cancer
Breast Cancer
Pancreatic Cancer
Mesothelioma
Thymic Carcinoma
Cervical Cancer
Ovarian Cancer
Bladder Cancer
Esophageal Cancer
Uterine Cancer
Sarcoma
Any Solid Tumors Progressed After a Prior Immunotherapy
Thymoma
Appendiceal Cancer
Olfactory Neuroblastoma
Keywords: TrkA
NTRK1
Head and Neck Carcinoma
Adenoid Cystic Carcinoma
Cervical Cancer
Breast Cancer
Lung Cancer
Non-Small Cell Lung Cancer
NSCLC
Mesothelioma
Sarcoma
Thymic
Thymoma
Pancreatic
Progression after anti PD-1/PD-L1 immunotherapy
Progressed after an immunotherapy
Ovarian
Bladder Cancer
Esophageal
Uterine
Olfactory Neuroblastoma
Appendiceal Cancer
Lead sponsor: VM Oncology, LLC
Sponsor class: INDUSTRY
First posted: 2018-06-14
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: * Dose Escalation: Tablet formulation (ongoing); Capsule formulation (complete)
* Cohort Expansion with RP2D;
Primary purpose: TREATMENT

Brief summary: This is a multicenter, open-label, Phase 1 study of orally administered VMD-928 in adult subjects with advanced solid tumors or lymphoma that have progressed or are non responsive to available therapies and for which no standard or available curative therapy exists

Detailed description: This is an open-label, Phase I, FTIH, multiple-dose, dose-escalation and cohort expansion multi-center study conducted in three parts to identify a safe and pharmacologically active dose and regimen for VMD-928 monotherapy, which can be implemented in Phase 2 studies (the RP2D). The regimen will be identified using an adaptive design, multiple-ascending dose study in cancer patients. To conserve patients in the lower dose cohorts, dose escalation will begin with an accelerated titration scheme. A second part of the study will assess antitumor activity at the RP2D. The third part of the study will collect tumor samples before and after treatment to assess biological activity.

Eligibility criteria: Key Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of any type of solid tumor malignancy or lymphoma that is not responsive to standard therapies or had progressed following standard therapy and for which there is no approved or curative therapy. Additionally, patients must not be candidates for or have exhausted regimens known to provide clinical benefit, including hematopoietic stem cell transplantation in lymphoma patients if they are deemed transplant eligible.
* ECOG score of 0 or 1.
* Able to swallow and retain oral medication.
* Adequate organ system function.
* Subjects must either have available archival tumor tissue samples, or consent to tumor tissue sampling prior to the first dose, that is sufficient for IHC analysis of TrkA expression, except with prior documented NTRK+.
* Subjects must have a tumor:

  (i). with TrkA protein overexpression (TrkA+) in the validated TrkA IHC assay, OR (ii). with documented NTRK1 gene fusion (NTRK1+) including a tumor which has progressed due to NTRK1 mutation after treatment of a pan-Trk inhibitor (e.g. larotrectinib or entrectinib)
* Adequate organ system function as defined as follows:

  1. Absolute neutrophil count ≥1.5x10\^9/L
  2. Hemoglobin ≥9g/dL
  3. Platelets ≥100x10\^9/L
  4. PT/INR, PTT ≤1.5xULN
  5. Total bilirubin ≤1.5x ULN
  6. AST, ALT ≤2.5xULN
  7. Creatinine ≤1.2xULN for age, weight
  8. Calculated creatinine clearance or 24h urine creatinine clearance ≥60mL/min

Key Exclusion Criteria:

1. Received chemotherapy having delayed toxicity within the last 14 days (six weeks for prior nitrosourea or mitomycin C).
2. Received anticancer therapy with radiation, immunotherapy, and a biologic, surgery and/or tumor embolization within the past 2 weeks.
3. Received an investigational anticancer drug within 14 days or 5 half-lives of the investigational agent, whichever is longer, prior to the first dose of VMD-928. Any exceptions to the above must be approved by the Sponsor Medical Monitor.
4. Unresolved toxicity from previous anticancer therapy \&amp;amp;amp;gt; CTCAE Grade 1 (except alopecia or anemia) unless agreed to by both the Sponsor Medical Monitor and the Investigator.
5. Negative result on TrkA immunohistochemistry (IHC) assay (if enrolled in dose expansion cohorts).
6. Known active infections including HIV disease.
7. Patients with a history of chronic viral hepatitis (HBV/HCV), even if treated, or a history of cirrhotic liver secondary to any etiology (i.e. alcoholism, non-alcoholic steatohepatitis).
8. Currently pregnant, nursing, or planning to become pregnant during the course of the study.
9. QTcF interval ≥ 480 msec.
10. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
11. Acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks.
12. Unstable or uncompensated respiratory, hepatic, renal, or cardiac disease that would compromise the patient's safety or interfere with assessment of the drug.
13. Psychological, familial, sociological, geographical, or other concurrent conditions that would interfere with safety evaluation, limit the patient's ability to follow the procedures in the protocol or otherwise jeopardize compliance with the protocol. Patients with uncontrolled major depression, bipolar disorder, or severe anxiety disorder are excluded.
14. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drug, or excipients.
15. Patient has had or is currently having other malignant tumors within 3 years.
16. Patients have multiple factors that affect their oral medication.
17. Patients have long-term unhealed wounds or fractures.
18. Patients have uncontrolled pleural effusion, pericardial effusion, or ascites that still require repeated drainage.
19. Patients are taking the following drugs and can't stop them during the study:

    * Tylenol or medicine containing acetaminophen (paracetamol).
    * Strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.

Primary outcomes:
measure: Number and severity of treatment-emergent AEs
timeFrame: Within 2 cycles (each cycle is 28 days)
Secondary outcomes:
measure: Area under the plasma concentration versus time curve (AUC) of VMD-928.
timeFrame: On Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
measure: Peak plasma concentration (Cmax) of VMD-928.
timeFrame: On Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
measure: Incidence of Dose Limiting Toxicities.
timeFrame: During the Cycle 1 (each cycle is 28 days)
measure: Analgesic response as defined by the Brief Pain Inventory (BPI).
timeFrame: On Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
measure: Change in TrkA protein expression.
timeFrame: Pre-dose and at the end of Cycle 2 (each cycle is 28 days)
measure: Correlation between clinical antitumor and AUC.
timeFrame: Up to the end of the Cycle 2 (each cycle is 28 days)
measure: Correlation between clinical antitumor and TrkA protein expression.
timeFrame: Up to the end of the Cycle 2 (each cycle is 28 days)
measure: Correlation between analgesic response and TrkA protein expression.
timeFrame: Up to the end of the Cycle 2 (each cycle is 28 days)
measure: Correlation between analgesic response and AUC.
timeFrame: Up to the end of the Cycle 2 (each cycle is 28 days)
Other outcomes:
Locations:
city: Santa Rosa
country: United States
facility: Providence Medical Foundation (site 209)
state: California
city: Hartford
country: United States
facility: Hartford Hospital (site 210)
state: Connecticut
city: Washington
country: United States
facility: The George Washington University Cancer Center (site 212)
state: District of Columbia
city: Pembroke Pines
country: United States
facility: Memorial Cancer Institute at Memorial Healthcare Systems (site 132)
state: Florida
city: Englewood
country: United States
facility: Englewood Hospital and Medical Center (site 202)
state: New Jersey
city: Florham Park
country: United States
facility: Summit Medical Group (site 205)
state: New Jersey
city: Morristown
country: United States
facility: Atlantic Health System, Morristown Medical Center (site 124)
state: New Jersey
city: Albuquerque
country: United States
facility: Presbyterian Kaseman Hospital (site 208)
state: New Mexico
city: New York
country: United States
facility: Weill Cornell Medicine, Cornell University (site 126)
state: New York
city: Maumee
country: United States
facility: Taylor Cancer Research Center (site 204)
state: Ohio
city: York
country: United States
facility: Cancer Care Associates of York (site 206)
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center (site 127)
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists (site 203)
state: Utah
city: San Juan
country: Puerto Rico
facility: PanOncology Trials, Hospital Oncologico - Puerto Rico Medical Center, Río Piedras (site 200)
Study officials:
affiliation: VM Oncology
name: Clinical Development
role: STUDY_CHAIR
References: