A First-in-Human (FIH) Study to Evaluate the Safety and Tolerability of VVD-130037 in Participants With Advanced Solid Tumors

Official title

A Phase 1, Open-label, Multicenter, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Activity of VVD-130037, a Kelch-like ECH Associated Protein 1 (KEAP1) Activator, in Participants With Advanced Solid Tumors

Overview

A FIH dose escalation and dose expansion study to evaluate VVD-130037 in participants with advanced solid tumors as a single agent, and in combination with docetaxel, paclitaxel, or pembrolizumab.

Interventions

• Drug VVD-130037
  Oral tablets
• Drug Docetaxel
  IV infusion
• Drug Paclitaxel
  IV infusion
• Drug Pembrolizumab
  IV infusion

Primary outcome measures

• Part 1 (Dose Escalation): Incidence and Severity of Dose-limiting Toxicities (DLTs) During DLT Observation Period [Time frame: Part 1: Single Agent and Docetaxel/Pembrolizumab Combination Therapy: From Day 1 to Day 21 of Cycle 1 [cycle length=21 days] and Part 1: Paclitaxel Combination Therapy: From Day 1 to Day 28 of Cycle 1 [cycle length=28 days]]
• Part 2 (Dose Expansion): Number of Participants With AEs, Serious Adverse Events (SAEs), and Clinical Laboratory Abnormalities [Time frame: Up to approximately 4 years]

Secondary outcome measures (10)

• Part 1 (Dose Escalation): Number of Participants With AEs, SAEs, and Clinical Laboratory Abnormalities [Time frame: Up to approximately 4 years]
• Part 2 (Dose Expansion): Recommended Phase 2 Dose (RP2D) of VVD-130037 as a Single Agent and in Combination with Docetaxel, Paclitaxel, or Pembrolizumab [Time frame: Up to approximately 4 years]
• Part 2 (Dose Expansion): Overall Response Rate (ORR) [Time frame: Up to approximately 4 years]
• Part 2 (Dose Expansion): Duration of Response (DOR) [Time frame: Up to approximately 4 years]
• Part 2 (Dose Expansion): Progression-free Survival (PFS) [Time frame: Up to approximately 4 years]
• Part 2 (Dose Expansion): Disease Control Rate (DCR) [Time frame: Up to approximately 4 years]
• Parts 1 and 2 (Dose Escalation and Expansion): Area Under the Plasma Concentration-time Curve (AUC) of VVD-130037 [Time frame: Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy)]
• Parts 1 and 2 (Dose Escalation and Expansion): Maximum Observed Concentration (Cmax) of VVD-130037 [Time frame: Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy)]
• Parts 1 and 2 (Dose Escalation and Expansion): Apparent Terminal Half-life (T1/2) of VVD-130037 [Time frame: Parts 1 and 2: Predose and multiple timepoints post-dose from Cycle 1 Day 1 up to Cycle 5 Day 1 (cycle length=21 days for Single Agent and Docetaxel/Pembrolizumab Combination Therapy and cycle length=28 days for Paclitaxel Combination Therapy)]
• Parts 1 and 2 (Dose Escalation and Expansion): QT/Corrected QT (QTc) Interval and Other Electrocardiogram (ECG) Parameters [Time frame: Parts 1 and 2: Up to approximately 4 years]

Eligibility criteria

Key Inclusion Criteria for Parts 1 and 2:

• Histologically or cytologically confirmed metastatic or unresectable solid tumor.
• Measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as assessed by the Investigator.
• Have progressed on or after all prior standard-of-care therapies for metastatic disease.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
• Adequate organ and marrow function as defined in the protocol.

Additional Key Inclusion Criteria for Part 2:

• Participants with squamous non-small cell lung cancer (sqNSCLC) with or without nuclear factor erythroid 2-related factor 2 (NRF2 \[NFE2L2\]) and/or cullin 3 (CUL3) mutations.
• Participants with advanced sqNSCLC must be refractory to or have progressed on or after a platinum-based doublet regimen and an immune checkpoint inhibitor.
• Participants with advanced head and neck squamous cell carcinoma (HNSCC) must have received prior treatment with platinum-based chemotherapy, an immune checkpoint inhibitor (for tumors with known programmed death-ligand 1 \[PD-L1\] expression, microsatellite instability-high, or mismatch repair deficiency, and an anti-epidermal growth factor receptor agent) (Combination Expansion Cohort).
• Participants with advanced esophageal squamous cell carcinoma (ESCC) must have received prior treatment with platinum-based chemotherapy, an immune checkpoint inhibitor (for tumors with known PD-L1 expression) (Combination Expansion Cohort).
• Participants with a known driver mutation, including activating epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, should have progressed after appropriate targeted treatment.
• Participants with known human epidermal growth factor receptor 2 overexpression should have progressed after appropriate targeted treatment.

Key Exclusion Criteria for Parts 1 and 2:

• Participant is known to have a mutation that has no expectation of benefit from VVD-130037. Current such mutations include the following:

• KEAP1 nonsense mutation (any position)
• KEAP1 frameshift mutation (any position)
• Any unresolved toxicity Grade ≥2 per CTCAE version 5.0 from previous anticancer treatment.
• Current or prior treatment with anti-epileptic medications for the treatment or prophylaxis of seizures.
• History of seizure or condition that may predispose to seizure.
• History or presence of central nervous system (CNS) metastases or spinal cord compression.
• Uncontrolled arterial hypertension despite optimal medical management.
• Risk factors for abnormal heart rhythm/QT prolongation as defined in the protocol.
• History of the following cardiac diseases:

i) congestive heart failure (New York Heart Association \[NYHA\] Class >II), ii) unstable angina, iii) new onset angina within past 6 months, iv) myocardial Infarction within the past 6 months, v) clinically significant arrhythmias within past 6 months.

• Any prior toxicity (Grade 3 or 4) related to immunotherapy leading to treatment discontinuation (Combination Expansion Cohort)
• Medical history of (noninfectious) pneumonitis/interstitial lung disease (ILD), drug induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active pneumonitis/ILD (Combination Expansion Cohort)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

South Korea · 9 centers

• National Cancer Center — Goyang
• The Catholic University of Korea, St. Vincent's Hospital — Goyang
• Gachon University Gil Medical Center — Incheon
• Seoul National University; Bundang Hospital — Seongnam
• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul
• Seoul National University Hospital — Seoul
• Severance Hospital; Yonsei University Health System — Seoul
• … and 1 more center

Spain · 9 centers

• Hospital Vall d'Hebron — Barcelona
• START Barcelona Hospital HM Nou Delfos — Barcelona
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Universitario Ramon y Cajal — Madrid
• NEXT Madrid — Madrid
• START Madrid CIOCC — Madrid
• Start Madrid-FJD, Hospital Fundacion Jimenez Diaz — Madrid
• Clinica Universitaria de Navarra — Pamplona
• … and 1 more center

United States · 8 centers

• Mayo Clinic Jacksonville — Jacksonville
• Florida Cancer Specialists — Sarasota
• Moffitt Cancer Center — Tampa
• Mayo Clinic Rochester — Rochester
• Sarah Cannon Research Institute — Nashville
• MDACC — Houston
• NEXT Dallas — Irving
• NEXT Virginia — Fairfax

Publications

• Roy N, Wyseure T, Lo IC, Lu J, Eissler CL, Bernard SM, Bok I, Snead AN, Parker A, Lo UG, Green JC, Inloes J, Jacinto SR, Kuenzi B, Pariollaud M, Negri K, Le K, Horning BD, Ibrahim N, Grabow S, Panda H, Bhatt DP, Wilkerson EM, Saeidi S, Zolkind P, Rush Z, Williams HN, Walton E, Pastuszka MK, Sigler JJ, Tran E, Hee K, McLaughlin J, Ambrus-Aikelin G, Pollock J, Abraham RT, Kinsella TM, Simon GM, Majo PMID 41417010

Identifiers

NCT: NCT05954312 · VVD-130037-001 · 2023-506199-28-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗