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
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.
Part-1 Dose Escalation [Key Inclusion]:
- Histologically or cytologically confirmed diagnosis of solid tumor malignancy or
lymphoma that is not responsive to standard therapies, are unfit for standard
chemotherapy or for which there is no approved or curative therapy.
- ECOG score of 0 or 1.
- Able to swallow and retain oral medication.
- Adequate organ system function.
Parts 2-4 Cohort Expansion Only [Key Inclusion]:
- Part 1 inclusion criteria.
- 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, AND have a tumor or tumor type in one of the following categories:
(i). Tumors showing a response or stable disease after at least 2 cycles of VMD-928
during Part 1;
(ii). Tumor types associated with high TrkA protein overexpression, i.e.:
- Thymic carcinoma and thymoma
- Mesothelioma
- Head and neck squamous cell carcinoma (HNSCC)
- Ovarian cancer (especially serous)
- Hepatocellular carcinoma
- Squamous cell carcinoma of lung (squamous NSCLC)
- Esophageal cancer
- Adenoid cystic carcinoma
- Prostate cancer
- Cervical cancer
- Gastric cancer
- Melanoma
- Acute myeloid leukemia
- Pancreatic carcinoma
- Non-Hodgkins' lymphoma
(iii). Tumors with documented NTRK1 gene fusions or amplifications, or TrkA protein
overexpression, or a tumor which has progressed due to NTRK1 mutation after treatment of a
pan-Trk inhibitor (e.g. larotrectinib or entrectinib)
Part 3 Pharmacodynamic Activity only (Eligible subjects in Part 2 may enroll in Part 3):
- Part-2 inclusion criteria.
- Tumor with readily accessible lesion that is amenable to biopsy and consent to pre-and
post-dose biopsy.
Part 4 Exploratory Comparative PK of Tablet vs. Capsule Formulations only (Eligible
subjects in Part 2 or 3 will be encouraged to enroll in Part 4)
Key Exclusion Criteria (Parts 1-4):
1. Received chemotherapy having delayed toxicity within the last 21 days (six weeks for
prior nitrosourea or mitomycin C).
2. Received anticancer therapy with radiation, immunotherapy, a biologic, surgery and/or
tumor embolization within the past 2 weeks.
3. Received an investigational anti-cancer drug within 21 days or 5 half-lives of the
investigational agent prior, whichever is longer, to the first dose of VMD-928.
4. Unresolved toxicity from previous anti-cancer therapy ≥ CTCAE Grade 1 (except alopecia
or anemia) unless agreed to by both the Investigator and Sponsor.
5. Negative result on TrkA-specific or pan-Trk IHC assay (Parts 2-4 only).
6. Known active infections including HIV disease.
7. Currently pregnant, nursing, or planning to become pregnant during the course of the
study.
8. QTcF interval ≥ 480 msec.
9. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system.
10. Acute coronary syndromes (including unstable angina), coronary angioplasty, or
stenting within the past 24 weeks.
11. Unstable or uncompensated respiratory, hepatic, renal, or cardiac disease that would
compromise the patient's safety or interfere with assessment of the drug.
12. Psychological, familial, sociological, geographical or other concurrent conditions
that would interfere with safety evaluation, limit the subject's ability to follow the
procedures in the protocol or otherwise jeopardize compliance with the protocol.
Subjects with uncontrolled major depression, bipolar disorder, or severe anxiety
disorder are excluded.
Key Exclusion Criteria (For Parts 1 and 4 only):
13. Any current medical condition that would alter the absorption, distribution,
metabolism or excretion of VMD-928 including but not limited to:
- Severe uncontrolled nausea or vomiting
- Severe uncontrolled diarrhea
- With a history of short bowel syndrome
- Clinically diagnosed malabsorption secondary to bowel resection
