Clinical trial NCT05415072: A Phase I/II Study of DYP688 in Patients With Metastatic Uveal Melanoma and Other GNAQ/11 Mutant Melanomas
Official title: A Phase I/II, Multi-center, Open Label Study of DYP688 in Patients With Metastatic Uveal Melanoma (MUM) and Other GNAQ/11 Mutant Melanomas
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastatic Uveal Melanoma
Keywords: Phase I/II
DYP688
melanoma
GNAQ/11 mutations
cancer
malignant melanoma
eye cancer
ocular melanoma
uveal melanoma
cutaneous melanoma
mucosal melanoma
neoplasms, eye
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-06-10
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase I (Dose Escalation): Incidence and severity of dose limiting toxicities (DLTs) during the first 28 days of treatment.
timeFrame: 28 days
measure: Phase I (Dose Escalation): Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: 9 months
measure: Phase I (Dose Escalation): Frequency of dose interruptions, reductions, and discontinuations
timeFrame: 9 months
measure: Phase II: Overall Response rate (ORR) per RECIST 1.1
timeFrame: 17 months
Secondary outcomes:
measure: Phase I and Phase II: PK profile of DYP688 - Area under the concentration-time curve (AUC)
timeFrame: 26 months
measure: Phase I and Phase II: PK profile of DYP688 - Peak concentration (Cmax)
timeFrame: 26 months
measure: Phase I and Phase II: PK profile of DYP688 - Total body clearance (CL)
timeFrame: 26 months
measure: Phase I and Phase II: PK profile of DYP688 - Elimination half-life
timeFrame: 26 months
measure: Phase I and Phase II: Prevalence and incidence of anti-DYP688 antibodies
timeFrame: 26 months
measure: Phase I (Dose Escalation): Best Overall Response (BOR) per RECIST v1.1
timeFrame: 9 months
measure: Phase I (Dose Escalation): Overall Response Rate (ORR) per RECIST v1.1
timeFrame: 17 months
measure: Phase II: Duration of response (DoR) per RECIST v1.1
timeFrame: 17 months
measure: Phase II: Progression free survival (PFS) per RECIST v1.1
timeFrame: 17 months
measure: Phase II: Disease Control Rate (DCR) per RECIST v1.1
timeFrame: 17 months
measure: Phase II: Overall Survival (OS)
timeFrame: 17 months
measure: Phase II: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: 17 months
measure: Phase II: Frequency of dose interruptions, reductions, and discontinuations
timeFrame: 17 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital Hematology Oncology
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center- New York Presbyterian Onc Dept
state: New York
city: New York
country: United States
facility: Memorial Sloane Kettering Cancer Center MSKCC
state: New York
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Paris
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
Study officials:
References: