Early this month, representatives from ACIS attended the annual American Society of Clinical Oncology (ASCO for short) conference. Here are the highlights in the Ocular Melanoma field from our Director of Research Kevin O’Neil.
Summary of Presentations and Posters in Uveal/Ocular Melanoma at the
American Society of Clinical Oncology (ASCO) Annual Meeting Chicago – June 3-7, 2023
During our participation in this year’s ASCO Annual Meeting, we identified scientific presentations totaling
12 novel therapies in development for patients with metastatic ocular/uveal melanoma.
As you read through the following summaries, we focus on reporting “Objective Remissions” which are
either Complete Responses (CR) or Partial Responses (PR; at least 30% reduction in tumor size) and
Stable Disease (SD; no significant change in tumor size since initiating therapy). The duration of objective response or stable disease is also a very important factor, which may then become Progression-Free Survival (PFS). This is truly a hopeful time in our disease, with many new therapeutic options now in clinical trials,
for further discussion on your possible eligibility with your medical oncologist. See: https://clinicaltrials.gov/
ACIS also attended an ASCO-invited, private session for patient advocates with Dr. Richard Pazdur
and his Office of Clinical Excellence at FDA. We urged the dozens of present FDA OCE physicians and staff members to consider durable PR and Stable Disease as early measures of efficacy in rare and progressive cancers, such as metastatic ocular/uveal melanoma. The FDA Office will hold a special workshop on “Early Endpoints for Registration” for novel therapies in July 2023, and we will attend in-person to provide further input on the real-world importance of durable Stable Disease (if not remissions) to patients and their families.
ACIS also met with Delcath Systems, who have an investigational “percutaneous hepatic perfusion” (PHP) therapy now filed with FDA for consideration of marketing approval this summer, in liver-dominant metastatic uveal melanoma. Delcath continues to offer their Expanded Access Program during this time of regulatory review, which is open for patients at Moffitt Cancer Center in Tampa, Duke Univ. in Durham and the
Univ. of Tennessee in Memphis: https://clinicaltrials.gov/ct2/show/NCT05022901?term=delcath&cond=Uveal+Melanoma%2C+Metastatic&cntry=US&draw=2&rank=1
On the last day of ASCO, Melody and Hanna attended a live Educational Session entitled:
“The Changing Landscape of Uveal Melanoma” presented by Sophie Piperno-Neumann, MD
from Institute Curie in Paris (a leading EU UM/OM clinical center). Here are the highlights of novel cancer agents in development in Europe and the US for patients with metastatic UM/OM:
- PLUME Phase II study (Paris): levatinib (VEGF inhibitor) + pembrolizumab (immune checkpoint inhibitor)
Ongoing: 25 metastatic UM/OM patients enrolled since Aug. 2022, stratified for patients with or without
prior tebentafusp· Phase I/II in EU/US for DYP688 (PMEL17 antibody conjugated with “GNAQ/11 inhibitor” molecule)
In metastatic UM/Om patients, after Phase I dose escalation results, Phase II will stratify by prior/no prior
tebentafusp - Phase I/II I US/UK for IMC-F106C (new ImmTAC targeting HLAA*02:01 antigen and PRAME on UM/OM cells)
So far, Partial Response in 3 of 6 PRAME positive metastatic UM/OM patients with no prior tebenetafusp,
but only minor/no response in 5 patients with prior tebentafusp· Phase II in US for IDE-196 ‘darovasertib’ (PKC inhibitor) in combination with crizotinib (ALK/ROS1 inhibitor)
Ideaya posted initial data for 25 metastatic UM/OM patients, and Dr. Piperno-Neumann provided an update
on 35 patients now enrolled: 11 (31%) confirmed Partial Response, 2 (6%) unconfirmed PR,
16 (46%) Stable Disease.
A Cure In Sight does not offer treatment recommendations, and information provided here is not
an endorsement of specific clinical trials, investigational drugs or investigators/cancer centers.
- High-Interest Uveal/Ocular Melanoma Abstracts:
Abstract: 9527| Poster Bd #: 290
Preliminary safety and efficacy results from an open-label, multicenter, phase 1 study of RP2 (an HSV Type I encoding GM-CSF conjugated to anti-CTLA-4 HuMab) as a single agent and in combination with nivolumab in a cohort of patients with uveal melanoma. (Sponsor: Replimune)
Presenter: Joseph J. Sacco, PhD, MBChB | The Clatterbridge Cancer Centre and University of Liverpool
Results: As of December 30, 2022, 17 pts with uveal melanoma were enrolled (RP2 monotherapy, n = 3; RP2 + nivo, n = 14). The majority of pts received both anti–PD-1 and anti–CTLA-4 therapy (12/17, 70.6%) and 17.6% received ≥3 prior lines of therapy. The overall objective response rate for the 14 pts with sufficient follow up for analysis was 28.6% [4/14] (all partial responses [PRs]; RP2 monotherapy, 1/3; RP2 + nivo, 3/11). The disease control rate (partial response + stable disease [SD]) was 57.1% (8/14; 4 pts with SD in RP2 + nivo cohort). The median (range) duration of response at the data cut-off was 5.8 (1.7–14.7) months. The most common overall Grade 1–2 treatment-related adverse events (TRAEs; ≥20%) were pyrexia, chills, fatigue, and hypotension. The only Grade 3 TRAE occurring in > 1 pt was hypotension (2 pts receiving RP2 + nivo); no Grade 4–5 TRAEs were observed.
Preliminary RP2 monotherapy and RP2 + nivo data demonstrated a favorable safety profile and meaningful antitumor activity in pts with metastatic uveal melanoma, an immunologically cold tumor with few effective treatment options. These data continue to support the hypothesis that IT oncolytic immunotherapy expressing anti–CTLA-4 in combination with anti–PD-1 may provide clinically meaningful benefit in pts with hard-to-treat/unresponsive tumors. Clinical trial information: NCT04336241
Abstract: 2521| Poster Bd #: 363
Safety and early biologic effects of phase 1 PERIO-01 trial of pressure-enabled drug delivery (PEDD) of TLR9 agonist
SD-101 and immune checkpoint inhibition (ICI) in uveal melanoma metastatic to the liver (MUM).
Presenter: Kamaneh Montazeri, MD | Massachusetts General Hospital (Sponsor: TriSalus)
Delivery barriers due to intratumoral pressure and immunosuppression related to myeloid-derived suppressor cells (MDSC) in liver tumors have created challenges for immunotherapy. TLR9 agonists seem to improve response to ICI. PERIO-01 is a first-in-man trial of PEDD of SD-101 using hepatic arterial infusion (HAI) with ICI in MUM.
Methods: PERIO-01 is an open-label phase 1 trial of SD-101 given by HAI in MUM (NCT04935229). The study consists of dose-escalation cohorts of SD-101 alone (Cohort A), with nivolumab (Cohort B), or nivolumab + ipilimumab (Cohort C). SD-101 is delivered over 2 cycles, with 3 weekly doses per cycle. Blood, liver metastasis (LM) and normal liver biopsies are collected for correlative studies.
Results: At data cutoff, 33 patients were enrolled, 30 of whom received at least one dose of SD-101, 13 in Cohort A (2, 4, and 8 mg), 15 patients in Cohort B (2 mg and 4 mg) and 2 patients in Cohort C (2 mg). The median age was 63 years of equal gender. Only 3 patients were treatment-naïve and 2 were HLA-A*-02:01+ who received prior tebentafusp.
Nine subjects had 4-7 Liver Mets and 4 had > 10. The median index LM size was 4.7 cm. Only one patient experienced a grade ≥3 adverse event (AE) related to SD-101, which was increased liver enzymes. All AEs related to cytokine release syndrome have been low-grade with the most common being fever (9), chills (5), and dizziness (4). Treatment resulted in high liver drug levels (median at 2 mg = 1540 ng/g and 8 mg = 2325 ng/g, p = 0.035), with only transient exposure in the periphery ( < 4 hours) and a maximum peak serum level of 554 mg/ml 30 minutes post-infusion. Increases in serum IL-18 and IFNγ were noted, with highest levels at 8 mg. Expansion of natural killer cells were detected in 9 of 10 patients from flow cytometry data peripherally. Monocytic MDSC levels were decreased in 5 of 5 patients on immune-fluorescence, and NanoString analysis revealed decreases in ARG-1 and IDO-1 gene levels up to 100 days from initial treatment. Broad immunostimulatory gene expression changes were noted in tumor and normal liver following SD-101, including increases in IFNB1 and IL-9. Using the available samples from 13 patients, 7 of 10 had decrease in ctDNA,
with complete clearance in 3, along with circulating tumor cell decreases in 6 of 13. In cohort B at 2 mg, 5 of 6 with available response data have stable disease with a median duration of disease control of 12 weeks (range = 7.5-24)
at data cutoff. NOTE: The poster presentation during ASCO updated Stable Disease to 16 of 25 (64%)
of metastatic UM/OM patients. The Phase II portion of the study will initiate later in 2023.
Conclusions: HAI of SD-101 has been well tolerated and associated with encouraging immunologic activity. Evidence of biologic effects at the lower doses of SD-101 with nivolumab is encouraging and enrollment with escalation continues in Cohorts B and C. Clinical trial information: NCT04935229.
Abstract: 3110 | Poster Bd #: 308
First-in-human (FIH) phase I dose escalation study (part A) of the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) roginolisib (IOA-244) in patients with advanced cancer and dose confirmation in uveal melanoma (part B). Presenter: Anna Maria Di Giacomo, MD; Center for Immuno-Oncology, Univ. Hospital of Siena IT
Results: Part A Solid Tumour (completed): Sixteen pts were treated in 4 cohorts, each with 4 pts. Pts characteristics:
uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%).
Only Grade 1 and 2 AEs by CTCAE v5 were observed, including 2 cases of transient (lasting < 24 hrs) diarrhea and
2 of AST/ALT elevation. Part A FL Cohort (completed): 8 pts were treated at 20 mg (n=4) and 80 mg (n=4). Grade 3 toxicities were transient and observed in 2/8 (25%) pts. 2/4 pts (50%) at the 80 mg had PR as per Lugano criteria.
Neither in the solid tumour nor in the haematology pts treatment-emergent adverse events (TEAE) led to study drug discontinuation, immune related toxicity, or a Dose Limiting Toxicity. Subgroup evaluation: UM pts (Part A and Part B):
24 pts (Part A: 9 pts; Part B ongoing: 15 pts), of which 18 pts treated at 80 mg QD (RP2D). Mean time on treatment:
8.6 mo (range: 1.0-27.9 mo). ORR (RECIST 1.1): PR: 1/20 (5%); SD: 16/20 (80%). Median OS for Part A: 20.8 mo
(5/9 with 4 pts alive); Part B: not determined; 1-year OS rate: Part A 66.7%; Part B: ongoing. Exploratory Investigations: Radiomics-based evaluation of CT images in pts with solid tumors assessed each metastatic organ, detecting mixed responses; peripheral proteomic evaluation detected changes in several cytokines and chemokines; CyTOF detected reduction in circulating Tregs associated with increased activated effector CD8+ T cells.
Roginolisib is well tolerated at the 80 mg dose, shows signs of efficacy and induces phenotypic changes in the circulating immune cells. As best response at the RP2D, the most robust anti-tumour activity was observed in FL (50% PR) and
UM pts (5% PR; 80% SD). Clinical trial information: NCT04328844.
Abstract: 9533 | Poster Bd #: 296
A phase I, randomized, controlled, multicentre trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab in patients with uveal melanoma metastases (the SCANDIUM 2 trial). Presenter: Roger Olofsson Bagge
Methods: Eligible in this multicenter open, randomized, controlled, phase I trial, were patients with liver dominant metastatic uveal melanoma who had not received previous systemic treatment. Patients were randomized to
receive either (Arm A) Isolated Hepatic Perfusion (IHP) followed by combination immunotherapy (four cycles IPI3/NIVO1 q3w) or (Arm B) one neoadjuvant cycle of IPI3/NIVO1 prior to IHP followed by three cycles IPI3/NIVO1 q3w.
Thereafter, both Arm A and B received monotherapy with nivolumab (480 mg q4w) for up to 1 year.
IHP was performed using melphalan 1mg/kg perfused through the liver for 60 minutes under hyperthermia (40°C).
The primary endpoint was incidence and severity of adverse events while, secondary endpoints included response according to RECIST v1.1 criteria reported according by the local investigator.
Results: A total of 18 patients were included and randomized, nine to Arm A and nine to Arm B. Three patients did not undergo IHP as planned, one due to perioperative complications (Arm A), one due to extensive metastatic liver infiltration ( > 50% liver volume) (Arm B) and one due to encephalitis related to neoadjuvant IPI3/NIVO1 (Arm B). A total of 20 serious adverse events (SAEs) were reported in eleven patients. There were ten SAEs in each arm, with no treatment related deaths. In total, 11 of 18 patients (six in Arm A and five in arm B) did not complete the planned four cycles of IPI3/NIVO1, with a mean of 2.4 cycles in Arm A and 3.0 cycles in Arm B. Response was evaluable in 17 patients, with the best clinical responses reported as three complete responses (18%), four partial responses (24%), seven stable disease (41%) and three progressive disease (18%). The overall response rate was 63% in Arm A (5/8) and 22% in Arm B (2/9).
Conclusions: For previously untreated patients with liver dominant metastatic uveal melanoma, treatment with IHP in combination with IPI3/NIVO1 had a high, yet manageable toxicity profile. The efficacy of this combination treatment is encouraging, however, one cycle of neoadjuvant IPI3/NIVO1 given before IHP did not seem beneficial, neither in regards to safety nor efficacy. Clinical trial information: NCT04463368
Abstract: LBA9512 | Poster Bd #: 275
Survival after isolated hepatic perfusion as a treatment for uveal melanoma liver metastases: Results from a randomized controlled trial (the SCANDIUM trial). (Data was released in slides during abstract presentation)
Presenter: Roger Olofsson Bagge, MD, PhD | Gothenburg University (IS THIS the DelCath system with melphalan??)
This randomized trial randomized and treated metastatic UM/OM patients to Isolated Hepatic Perfusion alone
(IHP; 43 patients) or Best Available Care (BAC; 44 patients). In the IHP group, 3 patients had Complete Response and 14 patients had Partial Response, with 7.4 months of Progression-Free Survival and 21.7 months of Overall Survival. The BAC group, 2 patients had obtained PR, with 3.3 months of PFS and 17.6 months of OS.
The ASCO reviewer noted across liver-regional therapy studies since 2014, there is variability and a disconnect of observed Objective Response rates and PFS when evaluating Overall Survival (not ‘significantly’ improved in this trial).
B. All Other Uveal/Ocular Melanoma Abstracts
Abstract: 9588 | Poster Bd#: 351
A phase Ib study of endogenous T cell therapy (ECT) using SLC45A2-specific CD8 T cells for patients with metastatic uveal melanoma. Presenter: Suzanne Phillips, MD Anderson/NCI
Between 6/2017 and 12/2022, we conducted a single-center, IRB-approved, first-in-human phase 1b dose escalation study of ETC targeting SLC45A2 in pts with metastatic UM (NCT03068624). Eligible pts with metastatic UM who express HLA-A*02:01 or A*24:02 underwent apheresis to collect peripheral T cells which were then selected and expanded (Turnstile 1). For Turnstile 2, conditioning with low-dose cyclophosphamide (300 mg/m2) occurred on Day -2. For pts in the radiation cohort, radiation occurred between Day -7 and Day -1. Infusion of ETC was done via hepatic arterial or central venous catheter on Day 0 followed by low dose subcutaneous interleukin-2 (IL-2) twice daily for 14 days +/- ipilimumab. The study utilized a 3+3 design with a starting dose level of 3.3 x 109 cells/m2 of ETC alone. The primary objective was to evaluate the safety and tolerability of infusing ETC targeting SLC45A2. Secondary objectives were to evaluate the in vivo persistence and anti-tumor efficacy of this regimen.
Results: With a median age of 58 years (30-77), 34 pts were enrolled, 16 (47%) men and 18 (53%) women. 33 (97%) pts underwent apheresis and 11 (32%) received infusion of ETC. One dose limiting toxicity (DLT) thought to be unrelated to treatment or underlying cancer (cardiac disorder Grade 5) occurred at the starting dose level with no additional DLTs.
The maximum tolerated dose was established as 1 x 1010 cells/m2. The most common treatment-related grade 3 and 4 toxicities were lymphocyte count decrease 9 (82%), hyponatremia 1 (9%), and hypophosphatemia 1 (9%). Per immune-related response criteria (irRC), 4 (36%) pts had stable disease (SD), 6 (55%) had progression of disease (PD), and 1 (9%) was not evaluable for best response. Median overall survival (OS) was 8.9 weeks (wks). OS was 91% at 4 wks, 55% at 8 wks and 46% at 13 wks. Median progression-free survival was 5.9 wks. In the 4 patients with stable disease, the median duration of SD was 5.7 months.
Conclusions: Targeting SLC45A2 is safe and well-tolerated in pts with metastatic UM. Further analyses are underway to evaluate T cell trafficking and persistence. Clinical trial information: NCT03068624.
Abstract: 9538 | Poster Bd# 301
Immune infiltrates in metastatic uveal melanoma liver metastases and associations with clinical outcomes.
Presenter: Katherine Emilie Rhoades Smith
Results: 140 patients with MUM who had pre-treatment liver biopsies were identified. 122 biopsies were evaluable for the presence of lymphocytes, either at the tumor-liver interface, or for Tumor Infiltrating Lymphocytes (TILs)s.
80/122 (65.6%) biopsies showed presence of any lymphocyte and 27/80 had TILs. 27 biopsies had sufficient tissue for further IHC classification. CD8+ T cells were identified in 27/27 samples, T cell PD1 positivity ≥1% in 4/27 samples, and regulatory T cell markers (CD25 and/or FoxP3) in 18/27 samples. Median OS for the entire cohort was 16 months (mo). Patients still alive at the time of data analysis had at least one year of follow-up available (range 13-124 mo). Univariate analyses (UVA) showed no significant improvement in Overall Survival based on the presence of any lymphocytes
(HR 1.01, p 0.98), lymphocytes at the tumor-liver interface (HR 1.10, p 0.64), TILs (HR 0.78, p 0.27), >50% CD8+ T cells (HR 0.88, p 0.77), or absence of FoxP3+ T cells (HR 0.68, p 0.40). In the 69 patients treated with ICIs (pembrolizumab, nivolumab, or ipilimumab plus nivolumab), neither the presence of any lymphocytes (HR 1.19, p 0.56) nor TILs (HR 0.68, p 0.24) were associated with an OS benefit.
Conclusions: We present a large cohort of patients with MUM where we characterized immune infiltrates in liver metastases and evaluated clinical outcomes. OS did not significantly improve with the presence of any lymphocytes, TILs, CD8+ T cells, or with the absence of FoxP3+ T cells. These results were consistent across all patients whether they were treated with ICIs or not. Our findings suggest that lymphocytes in MUM are functionally dormant and highlights the need for novel immune-activating treatment strategies.
Abstract: 9543 | Poster Bd #: 306
The effect of LNS8801 alone and in combination with pembrolizumab in patients with metastatic uveal melanoma.
Presenter: Alexander Noor Shoushtari (Sponsor: Linneaus Pharmaceuticals)
LNS8801 is an oral, selective, small molecule agonist of the G-protein coupled estrogen receptor (GPER). LNS8801 treatment results in increased melanocytic differentiation, reduced c-Myc protein levels in cancer cells, inhibition of proliferation, suppression of invasion, and enhancement of immune recognition. In preclinical models, LNS8801 has demonstrated increased activity in combination with immune checkpoint inhibitors (ICIs). In the first-in-human dose escalation study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab in patients with advanced solid tumors (NCT04130516).
Methods: Patients with measurable metastatic uveal melanoma (mUM) received LNS8801 (125 mg, QD, PO) alone or with pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective was safety and tolerability assessed according to NCI CTCAE v5.0. Secondary endpoints include pharmacokinetic, pharmacodynamics, objective response rate (ORR) and disease control rate (DCR, CR+PR+SD) per RECIST v1.1. Presence of a consensus, fully-functional, germline GPER coding sequence was assessed via Sanger sequencing on DNA extracted from blood as a potential predictive biomarker.
Results: As of 1/25/23, 15 patients with mUM were treated with LNS8801 alone/momotherapy (n = 8) or a combination of LNS8801 and pembrolizumab (n = 7). Patients were previously treated with a median of 2 prior lines of systemic therapy. 4 of 8 monotherapy patients had AEs potentially related to study drug (all grade 1), with no AEs occurring in more than one patient. 6 of 7 combination patients had AEs potentially related to study drugs (grades 1-2), with fatigue occurring in more than one patient. Of the 14 patients evaluable for efficacy (7 mono, 7 combo),
7 had disease control (4 mono, 3 combo) resulting in a disease control rate of 50%. 1 patient treated with combination achieved a confirmed partial response. Consensus germline GPER was present in 2 of 12 sequenced patients (1 mono, 1 combo), and both of these patients have ongoing disease control lasting longer than 24 weeks.
Conclusions: LNS8801 alone and in combination with pembrolizumab is tolerable without unanticipated toxicities and demonstrates encouraging anti-tumor activity in patients with mUM. The hypofunctional germline GPER variant appears over-represented in this cohort compared to the normal population, suggesting a potential significant role for GPER in the development of mUM. These data support further development of LNS8801 alone and in combination with pembrolizumab as a therapeutic approach to treat mUM patients, especially for patients with consensus germline GPER. Clinical trial information: NCT04130516.
Abstract: 9513 | Poster Bd #: 276
Tumor infiltrating lymphocyte (TIL) harvest and ex vivo expansion from primary and metastatic (met) uveal melanoma (UM) tumors. Presenter: Sapna Pradyuman Patel, MD | The University of Texas MD Anderson Cancer Center
Results: A total of 96 UM pts underwent TIL harvest; 9 underwent treatment with TIL. Median age was 54 years (range: 28 – 86); 56% of the pts were male; 78% were Caucasian, 9% Hispanic, and 13% unknown ethnicity. Overall successful ex vivo expansion of TIL occurred in 34.8% (32/92) of UM tumors in typical tumor fragment culture with IL-2 (TIL 1.0), with higher rates observed with UM mets (29/65; 44.6%) than UM primary tumors (3/27; 11.1%). Better results were observed with a culture method (TIL 3.0) that includes agonistic stimulation of CD3 and 41BB, with 96.8% (30/31 tumors). Expansion using this new method was successful in 9/10 primary UM tumors and 21/21 UM mets. Average number of days in culture for successful initial ex vivo expansion was 33.0 days for TIL 1.0 and 17.9 days for TIL 3.0 (p-value<0.0001). Overall, the average number of TIL expanded from culture and cryopreserved for clinical use was 130.4 million for TIL 1.0 (range: 34-460) and 326.2 million for TIL 3.0 (range 102-760) (p-value<0.0001). Nine met UM pts received treatment with up to 150 x 109 post-Rapid Expansion Protocol (REP) TIL (5 TIL 1.0, 4 TIL 3.0). Median age was 53, 44% were male, and all had active liver mets with a median of 3 lines of prior treatment for advanced disease. 8 of the TIL products were from UM mets (4 soft tissue, 3 liver, 1 combination of soft tissue and liver tumors), and 1 was from primary UM tumor, for which TIL could only be expanded with TIL 3.0. Best overall response rate per immune-related response criteria was 22% partial response (PR, duration of response was 22.1 months and 16.5 months), 44% stable disease (SD), and 33% progression of disease (PD) for a disease control rate of 66% (PR + SD). Both responding pts had TIL harvests from mets and had previously progressed on ICB, one was treated with TIL 3.0.
Conclusions: TIL harvest and successful ex vivo expansion of cells is possible from both primary and met UM with TIL 3.0 culture method and can be therapeutically effective. Clinical trial information: NCT00338377.
Abstract: 3008
A phase 1 study of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients (pts) with recurrent high-grade glioma or uveal melanoma (UM). Presenter: Varun Marga (Sponsor: Prelude Pharma)
Background: PRMT5 catalyzes symmetric arginine dimethylation of protein substrates and is involved in histone modification, transcription, and spliceosome assembly. PRT811 is a potent, selective, brain-penetrant PRMT5 inhibitor being studied in a phase 1, multicenter, open-label, dose-escalation and -expansion study in pts with advanced solid tumors, central nervous system lymphoma, and recurrent high-grade glioma (NCT04089449). Results from the dose-escalation phase have been previously presented. We report on the safety and efficacy of PRT811 in the dose-expansion phase for pts with recurrent high-grade glioma or UM, who have limited treatment (tx) options.
Methods: Eligible pts were aged ≥18 years, had an ECOG performance status (PS) of 0-1, adequate organ function, biopsy-confirmed recurrent high-grade glioma or UM, and were resistant, refractory, or ineligible to receive standard tx. Pts received 15-800 mg of PRT811 orally once daily (QD; 30 days = 1 cycle). The primary objectives were to evaluate the incidence of dose-limiting toxicities and determine the maximum tolerated/recommended phase 2 dose (RP2D) of PRT811. Key secondary objectives were to evaluate the safety, tolerability, and preliminary efficacy (per RECIST v1.1/RANO criteria) of PRT811.
Results: As of January 13, 2023, 86 pts were enrolled; of the 61 pts with recurrent high-grade glioma (n=38) or metastatic UM (MUM; n=23). 57.4% were female, 24.6% were aged ≥65 years, 91.4% had an ECOG PS of 0-1, and 8.2% were systemic therapy naive. Most pts (n=42) received the predicted RP2D of 600 mg QD and 19 pts received between 15 to 800 mg PRT811 QD. Overall, 13% of pts remain on tx. Most pts discontinued tx primarily due to disease progression (83.0%), adverse events (AEs; 5.7%), or pt withdrawal (5.7%). The most common tx-related AEs (mainly grade 1/2) were nausea (49.2%), vomiting (39.3%), fatigue (27.9%), constipation (14.8%), and thrombocytopenia (14.8%). The most common grade 3 tx-related AEs were thrombocytopenia (9.8%; reversible on tx interruption), anemia, fatigue, and lymphopenia (all 3.3%). No tx-related grade 4/5 serious AEs (investigator assessed) were observed; 2 pt deaths were unrelated to tx. Among the 16 IDH1/2-mutated (IDH+) pts with glioma, we observed 2 complete responses (CR; 1 ongoing, duration: 111+ weeks; 1 discontinued, duration: 33 weeks), 1 unconfirmed partial response (PR), and 8 pts with stable disease (SD). Among the 10 pts with MUM and a splicing gene mutation (SPLC+), 1 pt had a confirmed PR (duration: 43 weeks), 1 pt had an unconfirmed PR (ongoing), and 4 pts had SD. No CRs/PRs were observed in the 22 IDH– pts with glioma or 13 SPLC– pts with MUM. Additional follow-up data, including efficacy plots, will be presented.
Conclusions: PRT811 demonstrated an acceptable safety profile and clinical activity in pts with glioma and MUM.
Clinical trial information: NCT04089449.
A Cure In Sight does not offer treatment recommendations, and information provided here is not
an endorsement of specific clinical trials, investigational drugs or investigators/cancer centers.