Overview
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
Description
This is an open-label, Phase I, first-time-in-human, 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
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.
- Eastern Cooperative Oncology Group (ECOG) Performance Status: 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 [Vitrakvi®] or entrectinib [Rozlytrek®])
- Adequate organ system function as defined as follows:
- Absolute neutrophil count ≥1.5x10^9/L
- Hemoglobin ≥9g/dL
- Platelets ≥100x10^9/L
- PT/INR, PTT ≤1.5xULN
- Total bilirubin ≤1.5x ULN
- AST, ALT ≤2.5xULN
- Creatinine ≤1.2xULN for age, weight
- Calculated creatinine clearance or 24h urine creatinine clearance ≥60mL/min
Key Exclusion Criteria:
- Received chemotherapy having delayed toxicity within the last 14 days (six weeks for prior nitrosourea or mitomycin C).
- Received anticancer therapy with radiation, immunotherapy, and a biologic, surgery and/or tumor embolization within the past 2 weeks.
- 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.
- Unresolved toxicity from previous anticancer therapy > CTCAE Grade 1 (except alopecia or anemia) unless agreed to by both the Sponsor Medical Monitor and the Investigator.
- Negative result on TrkA immunohistochemistry (IHC) assay (if enrolled in dose expansion cohorts).
- Known active infections including HIV disease.
- 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).
- Currently pregnant, nursing, or planning to become pregnant during the course of the study.
- QTcF interval ≥ 480 msec.
- Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- Acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks.
- Unstable or uncompensated respiratory, hepatic, renal, or cardiac disease that would compromise the patient's safety or interfere with assessment of the drug.
- 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.
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drug, or excipients.
- Patient has had or is currently having other malignant tumors within 3 years.
- Patients have multiple factors that affect their oral medication.
- Patients have long-term unhealed wounds or fractures.
- Patients have uncontrolled pleural effusion, pericardial effusion, or ascites that still require repeated drainage.
- 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.