Bilic, Sanela

3082 Background: CLDN6, a member of the claudin family of tight junction proteins, is expressed at high levels in multiple human malignancies and has little to no expression in normal tissues. This expression profile makes CLDN6 an ideal target for development of new therapeutics. TORL-1-23 is first-in-class ADC targeting the tumor-specific antigen CLDN6. Methods: TORL123-001 (NCT05103683) is an ongoing, 2-part, first in human study to characterize the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of TORL-1-23 monotherapy in participants with advanced solid tumors. Serum pharmacokinetics (PK), immunogenicity and clinical efficacy are also assessed. TORL-1-23 is administered as a 30-minute IV infusion once every 3 weeks in 21-day cycles. During Part 1 (Dose Escalation), cohorts of 1 to 6 participants are evaluated at each dose level according to an accelerated titration design. In Part 2 (Dose Expansion), several cohorts of patients with CLDN6-expressing cancers will be evaluated to confirm the RP2D in ovarian cancer, NSCLC, and other CLDN6-expressing cancers using a CLDN6 IHC companion diagnostic. Results: As of 01FEB2023, 22 patients with ovarian (n=18), testicular (n=3), and endometrial (n=1) cancers were enrolled and treated across 8 dose levels ranging from 0.2 to 2.4 mg/kg IV every 3 weeks. 95% of pts had received ≥ 3 prior lines of treatment in the metastatic setting. The most common treatment-related adverse events were Gr1/2 fatigue (n=5), Gr1 peripheral neuropathy (n=4), and Gr1 nausea (n=3). No DLTs have been reported and no dose reductions have been required. Preliminary PK data demonstrate sustained exposure of TORL-1-23 ADC over the 21 day dosing interval and low levels of serum MMAE indicating low off-target MMAE exposure outside of tumor. Partial responses (PR) were observed in 4/17 efficacy evaluable participants with CLDN6+ disease (3 ovarian, 1 testicular). Dose escalation is ongoing and updated results will be presented. Conclusions: TORL-1-23 has a favorable safety/tolerability profile and PK characteristics with preliminary antitumor activity in pts with heavily-pretreated CLDN6-expressing ovarian and testicular cancers. Doses above the historic MTD for MMAE containing ADCs may be explored given the safety/tolerability and PK data observed up to 2.4 mg/kg. Dose finding is ongoing to identify the MTD and optimal doses for subsequent development. Clinical trial information: NCT05103683 .

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

Abstract Background: Despite many treatment options, multiple myeloma (MM) remains largely incurable with poor outcomes among patients who progress after treatment with a protease inhibitor, immunomodulatory imide drugs (IMiDs), and/or an anti-CD38 antibody. Multiple targeted therapies have been developed for different subtypes of non-Hodgkin lymphoma (NHL); however, these therapies are typically not curative for patients with relapsed/refractory (R/R) disease. IMiDs are a standard of care for treatment of MM and have shown activity in some NHL subtypes. However, given that many patients treated with these agents frequently develop disease progression, an unmet need remains. CFT7455 is a next-generation IKZF1/3 degrader, which is more potent and catalytically active than other approved agents targeting the cereblon E3 ligase complex that degrade IKZF1/3. CFT7455 is orally bioavailable and selective for IKZF1 (Ikaros) and IKZF3 (Aiolos). Depletion of these targets from malignant B cells result in tumor cell death, and depletion from the tumor microenvironment results in T-cell activation. In i n vitro and in vivo models of MM and NHL, including anaplastic large cell lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma (MCL), CFT7455 demonstrated greater activity than other agents in similar classes. These results provided rationale for a first-in-human, phase 1 study to evaluate CFT7455. Study Design: This is an open-label, multicenter, phase 1 clinical trial with dose escalation and dose expansion phases. The dose escalation phase, beginning with a starting dose of 50 mcg daily, may include single-participant cohorts at initial dose levels, after which 3-6 patients are enrolled per cohort using a Bayesian logistic regression model. After initial exploration of single-agent CFT7455 in a mixed cohort of patients with R/R MM or select NHLs, dose escalation is split to perform dose determination in R/R MM separate NHL. Once a safe dose of CFT7455 in R/R MM is determined, the combination of CFT7455 with dexamethasone will be explored in R/R MM. CFT7455 is dosed orally in 28-day cycles, on a 21-day on, 7-day off schedule, until disease progression or intolerable toxicity. Expansion cohorts of single-agent CFT7455 and CFT7455 plus dexamethasone in R/R MM, and single-agent CFT7455 for peripheral T-cell lymphoma and MCL are planned. Primary objectives include: safety and tolerability, randomized phase 2 dose (RP2D)/maximum tolerated dose (MTD) of CFT7455, and estimation of antitumor activity of CFT7455. Secondary objectives include assessment of pharmacokinetics. Exploratory objectives include characterization of target engagement and IKZF1/3 degradation and assessing the immunomodulatory effects of CFT7455. For MM patients, key inclusion criteria include histologically/cytologically-confirmed MM that is R/R. Patients must not be candidates for regimens known to provide clinical benefit, defined as having received ≥3 prior anti-myeloma regimens including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Plasma cell leukemia is excluded. For NHL patients, key inclusion criteria include histologically/cytologically-confirmed NHL that is R/R. Patients mustn't be candidates for regimens known to provide clinical benefit, defined as the requisite prior lines of therapy according to an indication-specific basis. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Several lymphoma subtypes less likely to benefit are excluded (eg, Richter transformation, Burkitt lymphoma, Sezary syndrome, and lymphoblastic lymphoma). Approximately 164 patients at approximately 13 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT04756726, enrollment is ongoing. Disclosures Berdeja: Legend Biotech: Consultancy; Incyte: Research Funding; Ichnos Sciences: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Lilly: Research Funding; SecuraBio: Consultancy; EMD Serono: Research Funding; Janssen: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Astex Pharmaceuticals: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Celularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; Takeda: Consultancy. Ailawadhi: GSK: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Xencor: Research Funding; Beigene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy; Medimmune: Research Funding. Horwitz: Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Tubulis: Consultancy; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Aileron: Research Funding; Vividion Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Celgene: Research Funding; Acrotech Biopharma: Consultancy; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Shoreline Biosciences, Inc.: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Verastem: Research Funding. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Martin: GlaxoSmithKline: Consultancy; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; Janssen: Research Funding. Richardson: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Richard: Karyopharm, Janssen: Honoraria. Bhutani: Sanofi: Consultancy; Amgen, BMS, Takeda: Speakers Bureau; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Yee: Takeda: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Palmer: C4 Therapeutics: Current Employment. Gorman: C4 Therapeutics: Current Employment. Schoenborn-Kellenberger: C4 Therapeutics: Current Employment. Bilic: C4 Therapeutics: Current Employment. Crystal: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mahler: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lonial: Merck: Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding.

Abstract Abstract 750 Background: DKK1 is a negative regulator of the Wnt signaling pathway in bone that is overexpressed in a subset of newly-diagnosed MM patients with osteolytic lesions as well as in refractory and relapsed patients. Expression also correlates with the number of osteolytic lesions in untreated MM patients. BHQ880 is a novel anti-DKK1 human monoclonal antibody. Alleviation of DKK1 inhibition by BHQ880 results in activation of the Wnt signaling pathway, leading to increased bone mass mediated via upregulation of osteoblasts in mice and monkeys. In murine models of MM bone disease; this anabolic activity of BHQ880 increased trabecular and cortical bone density. Lytic bone disease in MM is caused by osteoclast activation and osteoblast inhibition. Current approved therapies for the treatment of MM bone disease are focused on osteoclast inhibition (e.g., bisphosphonates) and BHQ880 therapy may be able to reverse the effects of DKK1-induced osteoblast inhibition. Therefore, dual therapy with zoledronic acid to decrease bone resorption and BHQ880 to increase new bone formation may provide an effective treatment strategy for MM bone disease. Methods: In the phase I portion of this phase I/II study, patients with relapsed or refractory MM with prior skeletal-related event (SRE) were treated with BHQ880 as an IV infusion Q28 days. Patients also received Zol (4 mg) and approved MM Tx (bortezomib not allowed). Bone markers and total DKK1 levels along with bone mineral density are being measured. Full PK profiles were collected during the first and second cycle, after which predose (trough) samples were collected to assess accumulation. Results: Ten pts (6:M, 4:F), median age: 66.5 yrs (range 41- 70), performance status-0(5 pts), 1(4 pts), 2 (1 pts) have been enrolled in the following dose levels (mg/kg) 3 (2 pts), 10 (starting dose level -4 pts), 20 (4 pts) and have been on treatment for 1 day to 5 28-day cycles. No BHQ880-related AE's have been observed to date. Bone mineral density (BMD) data from the first two patients treated at 10 mg show the following: a.) Pt 1 (hip +5.8%, spine N/A due to surgery, wrist -1.8%); b.) Pt 2 (hip -0.2%, spine +6.1%, wrist not done). The biomarker data from these patients show: a.) Pt 1 shows a maximal +98% change over baseline in PINP at day 15 post-treatment, while osteocalcin (OC) changes +17% at day 15, reaching a +56% change over baseline at cycle 4 day 1; uNTx/Cr changes – 43 % at cycle 2 day 15. b) Partial data from Pt 2 suggests a -44 % change in PINP and –73 % change in OC and a +73% change in uNTx/Cr. Baseline total DKK1 levels on 3 patients ranged from 8.8 to 21.5 ng/mL. Preliminary PK analysis is available in 1 out of 3 patients treated at 10mg/kg. The Cmax achieved after the first infusion was 165 ug/mL and 201 ug/mL after the second infusion. Calculated t1/2 was 188 hours after the first infusion and 254 hours after the second infusion. Regarding overall exposure, AUC0-672 hours after first infusion was 36081 hr*ng/mL and 48533 hr*ng/mL after the second infusion. Conclusion: BHQ880 given IV Q28 days appears to be well tolerated in combination with Zol and chosen MM Tx. Once safety of 40 mg/kg BHQ880 or the MTD dose has been determined, pts will be enrolled in the phase II portion to assess activity on a SRE endpoint. Updated safety, efficacy, bone density and biomarker data will be presented on all patients at the upcoming ASH meeting. Disclosures: Padmanabhan: Genentech: Consultancy, Honoraria; GSK: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Off Label Use: BHQ880, a novel osteoblast activating, anti-DKK1 antibody. Dzik-Jurasz:Novartis: Employment, Equity Ownership. Gangolli:Novartis: Employment, Equity Ownership. Ettenberg:Novartis: Employment, Equity Ownership. Miner:Novartis: Employment, Equity Ownership. Bilic:Novartis: Employment, Equity Ownership. Whyte:Novartis: Employment, Equity Ownership. Mehdi:Novartis: Employment, Equity Ownership. Chiang:Novartis: Employment, Equity Ownership. Rae:Novartis: Employment, Equity Ownership. Shah:Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Elan: Consultancy. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Stewart:Novartis: Consultancy; Amgen: Consultancy; Millenium: Consultancy, Research Funding; Proteolix: Consultancy; Celgene: Honoraria.

SummaryDickkopf‐1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti‐DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma‐related bone disease and as an agent with potential anti‐myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose‐limiting toxicity (DLT) of escalating doses in combination with anti‐myeloma therapy and zoledronic acid. Twenty‐eight patients were enrolled and received BHQ880 at doses of 3–40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal‐related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti‐myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.