Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Eye Diseases

Rare Diseases

Melanoma

Uveal Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Eye Neoplasms

Uveal Diseases

Intraocular Melanoma

Neuroendocrine Tumor

Neuroepithelioma

Up to approximately 125 patients will be enrolled in dose escalation and expansion

FHD-286

Sarah Reilly, MD

This Phase 1, multicenter, open-label, dose escalation and expansion study is designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FHD-286 oral monotherapy in subjects with metastatic Uveal Melanoma (UM).

This study is an ascending multiple dose clinical trial with expansion arms. It is primarily intended to evaluate the safety and tolerability of FHD-286 when administered orally to subjects with metastatic UM. The Dose Escalation Phase will allow for the determination of the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) in subjects with metastatic UM. This study will also evaluate the PK/PD profiles of multiple dose administration of FHD-286.

The Dose Expansion Phase will allow a more robust evaluation of the safety profile of FHD-286, including less frequent toxicities and an assessment of antitumor activity. The data from this study in subjects with metastatic UM, including safety, tolerability, PK/PD findings, and antitumor activity, will form the basis for subsequent clinical development of FHD-286.

Open label single arm dose escalation and two-arm expansion study in patients with metastatic UM

FHD-286 in Subjects With Metastatic Uveal Melanoma

A Phase 1, Multicenter, Open-Label, Dose Escalation and Expansion Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered FHD-286 in Subjects With Metastatic Uveal Melanoma

ORR is defined as the percentage of subjects with evidence of a complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.

DOR is defined as the time from first documented evidence of CR or PR until the earliest date of documented radiological progression per RECIST 1.1. or death due to any cause among subjects who achieved a CR or PR

TTR is defined as the period of time from the date of first study drug administration until the first objective documentation of a CR or PR per RECIST 1.1.

TTP is defined as the time from the date of first study drug administration until the start of disease progression per RECIST Version 1.1.

PFS defined as the time from first dose of study treatment until the first date of either objective disease progression per RECIST 1.1. or death due to any cause

OS is defined as the time from first dose of study treatment to the date of death, irrespective of the cause of death

Characterization of the PK profile of FHD-286

Plasma concentration of FHD-286 at the scheduled timepoints

Foghorn Therapeutics Inc.

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive PLX2853 PO in combination with trametinib PO throughout the study. Patients also undergo collection of blood at screening and on study. Patients also undergo CT or MRI with contrast and collection of blood at screening and on study.

BRD4 Inhibitor PLX2853

Computed Tomography

Magnetic Resonance Imaging

Biospecimen collection

This phase I/II trial tests the safety, side effects, and best dose of PLX2853 in combination with trametinib in treating patients with uveal (eye) melanoma that has spread to other places in the body (metastatic) or nearby tissues or lymph nodes (locally advanced), or that cannot be removed by surgery (unresectable). PLX2853 works by targeting and inhibiting certain activities within cells that promote tumor growth. By inhibiting these activities, PLX2853 may help to stabilize or reduce the growth of tumor cells. Trametinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving PLX2853 in combination with trametinib may help to shrink and stabilize tumor cells in patients with advanced uveal melanoma.

CO-PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose(s) (MTD(s)) and recommended phase II dose. (Phase I) II. To evaluate whether combination BRD4 inhibitor PLX2853 (PLX2853) and trametinib demonstrate clinical activity in advanced uveal melanoma (UM), as determined by a best response rate of 25% compared to a historical rate of 10%. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) associated with combination PLX2853 and trametinib.

II. To evaluate the progression-free survival (PFS) associated with combination PLX2853 and trametinib.

III. To evaluate the overall survival (OS) associated with combination PLX2853 and trametinib.

IV. To characterize the adverse event profile associated with combination PLX2853 and trametinib.

PHARMACOKINETICS SECONDARY OBJECTIVE:

I. To evaluate the pharmacokinetic profile of combination PLX2853 and trametinib.

OUTLINE: This is a phase I dose-escalation study of PLX2853 and trametinib followed by a phase II study.

Patients receive PLX2853 orally (PO) in combination with trametinib PO throughout the study. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) with contrast and collection of blood at screening and on study.

Testing the Safety and Effectiveness of Combining Two Drugs, PLX2853 and Trametinib in the Treatment of Advanced Uveal Melanoma

Phase I/II Study of BET and MEK Inhibition in Advanced Uveal Melanoma

Will be found using a Keyboard design which will be the dose with an estimated dose-limiting toxicity (DLT) rate closest to 25% (the target DLT rate).

Defined as the number of patients that achieve a best response of PR or better divided by the total number of evaluable patients. Will be evaluated using a Simon two-stage mini-max design using a historical response rate of 10% based on some prior work in this disease population with chemotherapy and targeted therapy. A 95% confidence interval for this estimate will also be calculated based on properties of the binomial distribution.

The Kaplan-Meier (KM) method will be used to estimate the median PFS time. A 95% confidence interval for the median PFS time will also be calculated using KM methodology.

Will be estimated using Kaplan-Meier method, and a 95% confidence interval will also be calculated using KM methodology.

The Kaplan-Meier method will be used to estimate the median PFS time. A 95% confidence interval for the median PFS time will also be calculated using KM methodology.

Adverse events will be recorded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 for each patient. Frequency tables and summary statistics will be used and with the appropriate methods of evaluating categorical and continuous data.

Systemic exposure to trametinib and PLX2853 will be assessed by determining trough plasma concentrations (Ctrough, Cmin), which is the concentration in a sample collected immediately prior to a next dose. Ctrough will be determined throughout the first two treatment cycles on day 1 and day 15. Ctrough of trametinib and PLX2853 will be summarized using descriptive statistics. Dose dependency of Ctrough in phase 1 will be investigated using exploratory statistics. Potential changes in systemic exposure to either trametinib and/or PLX2853 over time will be explored by investigating changes in Ctrough during the two cycles. In addition, will use population PK models combined with the Ctroughs to describe the full PK of trametinib and PLX2853.

Alliance for Clinical Trials in Oncology

Symptoms and General Pathology

Neoplasm Metastasis

Melphalan

Immunomodulating Agents

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

The effect of ipilimumab and nivolumab has previously been tested in metastatic uveal melanoma. In this study the combination with percutaneous hepatic perfusion will be performed in order to evaluate the effect.

Ipilimumab and nivolumab

Melphalan chemosaturation via percutaneous hepatic perfusion

Ellen W. Kapiteijn, MD, PhD

Mark C. Burgmans, MD, PhD

Ellen Kapiteijn, MD, PhD

Frank Speetjens, MD, PhD

Thaïs Tong, MD

Melanoma of the eye (ocular/uveal melanoma) is an uncommon type of cancer that is associated with a high mortality. It usually disseminates rapidly throughout the body, most commonly to the liver and lungs. In this study a combination therapy with immunotherapy (ipilimumab with nivolumab) and chemotherapy (melphalan) will be assessed for the treatment of disseminated uveal melanoma. Melphalan will be administered selectively to the liver via percutaneous hepatic perfusion, limiting the systemic effect of chemotherapy. With this treatment combination we aim to find a treatment for disseminated uveal melanoma, both in the liver as in the other organs.

Uveal melanoma (UM) is an uncommon malignancy (0.6-0.7 cases/100.000/year) that, in the case of metastatic stage, has a poor prognosis for response to treatment and survival. It is remarkable for its purely hematogenous pattern of dissemination, most commonly to the liver (60%) and lungs (25%). Current approaches using percutaneous hepatic perfusion (PHP) with melphalan resulted in response rates of up to 40% in the liver (1, 2) (for results of our own phase II study see paragraph 6.3.2). However, a main part of the patients developed extrahepatic disease in the follow-up, whereas the liver metastases were mainly stable.

Checkpoint inhibitors have been shown to improve overall survival in metastasized cutaneous melanoma in phase III studies (3-6), but seem to have limited activity as monotherapies in metastasized uveal melanoma (7-9). The combination of ipilimumab and nivolumab has achieved 2 out of 6 patients PR in a retrospective analysis (10). Interestingly, both patients had a liver-directed therapy (SIRT and chemoembolization) before the immunotherapy.

Combination of radio-frequency ablation (RFA) and anti-CTLA-4 enhanced antigen-loading of dendritic cells, and induced long-lasting anti-tumor immune responses in a murine melanoma model without induction of any severe side effects (11, 12). A phase Ib/II trial by Blank et al. (13) showed unconfirmed responses in some patients when RFA was combined with ipilimumab in uveal melanoma, but long-term disease stabilization was not achieved. Most of the responses were seen in extrahepatic metastases. Combining percutaneous hepatic perfusion (PHP) with checkpoint inhibitors could together lead to control of hepatic and extrahepatic disease. Therefore, we propose the current trial: Phase1b/2 Study Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced Uveal Melanoma (CHOPIN).

In the phase 1b part, safety and feasibility of combining percutaneous hepatic perfusion with 4 courses of ipilimumab and nivolumab will be investigated. In the randomized phase 2 part, efficacy as measured by progression-free survival at one year comparing PHP only versus PHP plus ipilimumab/nivolumab will be evaluated.

Open label, single center, phase Ib/randomized phase II trial, evaluating the safety and efficacy (as measured by RECIST 1.1) of the combination of PHP and ipilimumab/nivolumab in patients with unresectable hepatic and extrahepatic metastases of uveal melanoma.

PHP and Immunotherapy in Metastasized UM

Phase1b/2 Study Combining Hepatic Percutaneous Perfusion With Ipilimumab Plus Nivolumab in Advanced Uveal Melanoma

Dose limiting toxicities, maximum tolerated dose and recommended phase dose of the combination ipilimumab/nivolumab and PHP in patients with unresectable, histologically confirmed hepatic metastasis of uveal melanoma in phase Ib part.

Description of PFS according to RECIST 1.1 at one year in the PHP group versus PHP + ipilimumab/nivolumab group in the phase II part.

Description of response rate and overall survival, overall clinical response, and duration of response

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
FHD-286 in Subjects With Metastatic Uveal Melanoma	NCT04879017	Metastatic Uvea...	FHD-286	18 Years -	Foghorn Therapeutics Inc.
Testing the Safety and Effectiveness of Combining Two Drugs, PLX2853 and Trametinib in the Treatment of Advanced Uveal Melanoma	NCT05677373	Advanced Uveal ... Metastatic Uvea... Unresectable Uv...	BRD4 Inhibitor ... Trametinib Computed Tomogr... Magnetic Resona... Biospecimen col... Biospecimen col...	18 Years -	Alliance for Clinical Trials in Oncology
PHP and Immunotherapy in Metastasized UM	NCT04283890	Uveal Melanoma,...	Ipilimumab and ... Melphalan chemo...	18 Years - 75 Years	Leiden University Medical Center
PHP and Immunotherapy in Metastasized UM	NCT04283890	Uveal Melanoma,...	Ipilimumab and ... Melphalan chemo...	18 Years - 75 Years	Leiden University Medical Center
Testing the Safety and Effectiveness of Combining Two Drugs, PLX2853 and Trametinib in the Treatment of Advanced Uveal Melanoma	NCT05677373	Advanced Uveal ... Metastatic Uvea... Unresectable Uv...	BRD4 Inhibitor ... Trametinib Computed Tomogr... Magnetic Resona... Biospecimen col... Biospecimen col...	18 Years -	Alliance for Clinical Trials in Oncology

Spots Global Cancer Trial Database for advanced uveal melanoma