A Phase I/II Study of DYP688 in Patients With Metastatic Uveal Melanoma and Other GNAQ/11 Mutant Melanomas

A Phase I/II, Multi-center, Open Label Study of DYP688 in Patients With Metastatic Uveal Melanoma (MUM) and Other GNAQ/11 Mutant Melanomas

This is a FIH, phase I/II, open label, multi-center study of DYP688 as a single agent. The purpose of this study is to characterize the safety, tolerability, and anti-tumor activity of DYP688 as a single agent in patients with metastatic uveal melanoma (MUM) and other melanomas harboring GNAQ/11 mutations.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Uveal Melanoma
• Intervention / Treatment: Drug: DYP688

Detailed Description

This is a First in Human (FIH), phase I/II, open label, multi-center study of DYP688 as a single agent. There will be two parts to this study: a phase I, dose escalation part followed by a phase II part. Dose escalation will be conducted in patients with MUM and other melanomas harboring GNAQ/11 mutations. Once the MTD and/or RD(s) is determined in the dose escalation part, the study may continue with a phase II part. The phase II part will be conducted in two groups of patients with MUM, a prior tebentafusp-treated group and a tebentafusp-naïve group. In addition to MUM, a third group of patients with non-uveal GNAQ/11 mutant melanomas may also be explored. This cohort may be opened based on emerging data from the dose escalation part of the study.

• Study Type: Interventional
• Enrollment (Estimated): 124
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111; Email: novartis.email@novartis.com

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Recruiting
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • Novartis Investigative Site
• France
  • Paris, France, 75231
    • Recruiting
    • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Recruiting
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Recruiting
    • Novartis Investigative Site
• Netherlands
  • Leiden, Netherlands, 2300 RC
    • Recruiting
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28050
    • Recruiting
    • Novartis Investigative Site
• Switzerland
  • Zuerich, Switzerland, 8091
    • Recruiting
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital Hematology Oncology
      • Principal Investigator: Ryan Sullivan
      • Contact: Ryan Sullivan; Phone Number: 617-724-5197
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center- New York Presbyterian Onc Dept
      • Contact: Caitlin Rogers; Phone Number: 212-885-0878; Email: cr3311@cumc.columbia.edu
      • Principal Investigator: Alexander Wei
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloane Kettering Cancer Center MSKCC
      • Contact: Alexander Shoushtari; Email: shoushta@mskcc.org
      • Principal Investigator: Alexander Shoushtari

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients in the dose escalation part must be ≥ 18 years of age at the time of informed consent (ICF) signature. In the phase II part, patients ≥ 12 years of age at the time of informed consent may be eligible for enrollment (not applicable in countries where enrollment is restricted by the local health authority to patients ≥ 18 years of age). Patients must have a minimum weight of 40 kg.
• ECOG performance status ≤ 1 for patients ≥ 18 years of age; Karnofsky performance status ≥ 70 for patients ≥ 16 and < 18 years of age; Lansky performance status ≥ 70 for patients ≥ 12 and < 16 years of age
• Patients must be suitable and willing to undergo study required biopsies according to the treating institution's own guidelines and requirements. If a biopsy is not medically feasible, exceptions may be considered after documented discussion with Novartis.

For all patients in Dose Escalation

• MUM: uveal melanoma with histologically or cytologically confirmed metastatic disease. Patient must be either treatment naive or have received any number of prior lines and progressed on most recent therapy
• Non-MUM: advanced cutaneous or mucosal melanoma with histologically or cytologically confirmed metastatic disease that has progressed following all standard therapies or that has no satisfactory alternative therapies and has evidence of GNAQ/11 mutation based on local data

For patients in Phase II

• Tebentafusp naïve group: Diagnosis of uveal melanoma with histologically or cytologically confirmed metastatic disease that has progressed following standard therapies or that has no satisfactory alternative therapies
• Tebentafusp pre-treated group: Diagnosis of uveal melanoma with histologically or cytologically confirmed metastatic disease. Patients must be previously treated with tebentafusp and have progressed
• Non-MUM: patients with diagnosis of cutaneous or mucosal melanomas harboring GNAQ/11 mutations based on local data, with histologically or cytologically confirmed metastatic disease that has progressed following all standard therapies or that has no satisfactory alternative therapies

Exclusion Criteria:

• Malignant disease, other than that being treated in this study.
• Active brain metastases, i.e. symptomatic brain metastases or known leptomeningeal disease.
• Evidence of active bleeding or bleeding diathesis or significant coagulopathy (including familial) or a medical condition requiring long term systemic anticoagulation that would interfere with biopsies.
• History of anaphylactic or other severe hypersensitivity / infusion reactions to ADCs or monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction.

• Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:

  • 2 weeks for fluoropyrimidine therapy
  • 4 weeks for radiation therapy or limited field radiation for palliation within ≤ 2 weeks prior to the first dose of study treatment.
  • 4 weeks or ≤ 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
  • 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C.
  • 4 weeks for immuno-oncologic therapy, such as CTLA-4, PD-1, or PD-L1 antagonists.
• Clinically significant and / or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA grade ≥ 2) or clinically significant arrhythmia despite medical treatment.

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I: Dose Escalation; Patients with metastatic uveal melanoma or other GNAQ/11 mutant melanomas	Drug: DYP688; Single agent DYP688
Experimental: Phase II: Tebe naive group; Patients with metastatic uveal melanoma that has not received prior treatment with tebentafusp	Drug: DYP688; Single agent DYP688
Experimental: Phase II: Tebe pre-treated; Patients with metastatic uveal melanoma that have been previously treated with tebentafusp	Drug: DYP688; Single agent DYP688
Experimental: Phase II: Non-uveal melanoma; Optional Arm: To explore patients with non-uveal melanoma that harbor GNAQ or 11 mutations, based on emerging data from dose escalation	Drug: DYP688; Single agent DYP688

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I (Dose Escalation): Incidence and severity of dose limiting toxicities (DLTs) during the first 28 days of treatment.	A DLT is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications that occurs within the first cycle of treatment with DYP688. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.	28 days
Phase I (Dose Escalation): Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	Assessment of safety of DYP688 as a single agent	9 months
Phase I (Dose Escalation): Frequency of dose interruptions, reductions, and discontinuations	Assessment of tolerability of DYP688 as a single agent	9 months
Phase II: Overall Response rate (ORR) per RECIST 1.1	ORR in Phase II will be evaluated by central review per RECIST 1.1.	17 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I and Phase II: PK profile of DYP688 - Area under the concentration-time curve (AUC)	Pharmacokinetic (PK) parameters will be determined by non-compartmental methods using pharmacokinetic profile of DYP688.	26 months
Phase I and Phase II: PK profile of DYP688 - Peak concentration (Cmax)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of DYP688.	26 months
Phase I and Phase II: PK profile of DYP688 - Total body clearance (CL)	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of DYP688.	26 months
Phase I and Phase II: PK profile of DYP688 - Elimination half-life	Pharmacokinetic parameters will be determined by non-compartmental methods using pharmacokinetic profile of DYP688.	26 months
Phase I (Dose Escalation): Best Overall Response (BOR) per RECIST v1.1	Evaluation of preliminary anti-tumor activity of DYP688 as a single agent	9 months
Phase I (Dose Escalation): Overall Response Rate (ORR) per RECIST v1.1	Evaluation of preliminary anti-tumor activity of DYP688 as a single agent	17 months
Phase II: Duration of response (DoR) per RECIST v1.1	Evaluation of anti-tumor activity of DYP688 as a single agent	17 months
Phase II: Progression free survival (PFS) per RECIST v1.1	Evaluation of anti-tumor activity of DYP688 as a single agent	17 months
Phase II: Disease Control Rate (DCR) per RECIST v1.1	Evaluation of anti-tumor activity of DYP688 as a single agent	17 months
Phase II: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	Assessment of safety of DYP688 as a single agent	17 months
Phase II: Frequency of dose interruptions, reductions, and discontinuations	Assessment of tolerability of DYP688 as a single agent	17 months
Phase I and Phase II: Prevalence and incidence of anti-DYP688 antibodies	Assess of immunogenicity (IG) of DYP688 as a single agent	26 months
Phase II: Overall Survival (OS)	Evaluation of the effect of DYP688 as a single agent on overall survival	17 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 4, 2022
• Primary Completion (Estimated): March 12, 2026
• Study Completion (Estimated): March 13, 2026

Study Registration Dates

• First Submitted: June 8, 2022
• First Submitted That Met QC Criteria: June 8, 2022
• First Posted (Actual): June 10, 2022

Study Record Updates

• Last Update Posted (Actual): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: cancer; Phase I/II; DYP688; melanoma; GNAQ/11 mutations; malignant melanoma; eye cancer; ocular melanoma; uveal melanoma; cutaneous melanoma; mucosal melanoma; neoplasms, eye
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Eye Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Uveal Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Eye Neoplasms; Melanoma; Uveal Neoplasms
• Other Study ID Numbers: CDYP688A12101; 2021-003380-95 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No