Phase I study of CCW702, a bispecific small molecule-antibody conjugate targeting PSMA and CD3 in patients with metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5094-TPS5094
Author(s):  
Mark Christopher Markowski ◽  
Deepak Kilari ◽  
Mario A. Eisenberger ◽  
Rana R. McKay ◽  
Robert Dreicer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Small Molecule ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Unnatural Amino Acid ◽  
Castration Resistant Prostate Cancer ◽  
Antibody Drug Conjugate ◽  
Metastatic Setting

TPS5094 Background: CCW702 is a novel bispecific antibody comprised of a small molecule imaging agent ligand (DUPA) with specificity for prostate specific membrane antigen (PSMA) conjugated to an anti-CD3 antibody via an unnatural amino acid. This format has the structure of an antibody drug conjugate with the activity of a CD3-engaging bispecific antibody. The design of CCW702 was leveraged to optimize the structure and function of T cell redirected cytotoxicity against PSMA-positive prostate cancer tumors in preclinical development. Methods: This is a first-in-human, open-label, multi-center phase 1 study evaluating the safety and tolerability of CCW702 when administered via subcutaneous (SC) injection in men with mCPRC. This study will be conducted in two parts: Part I, a dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (R2PD); Part II, a dose expansion to determine efficacy at the R2PD. Safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy will be evaluated. Efficacy will be assessed by change in circulating tumor cells (CTC), PSA50 response rate, and objective tumor response by RECIST v1.1. Key biomarkers include characterization of CTC, T cell phenotyping in peripheral blood, chemokines and cytokines over time, and evaluation of available tumor biopsies by IHC. Key inclusion criteria include men age ≥ 18 years with histologically or cytologically confirmed adenocarcinoma who, in the metastatic setting, have progressed on at least one novel AR-targeted therapy. Up to 1 prior chemotherapy regimen is allowed. This study will enroll 20-30 patients in Part 1 and approximately 40 patients in Part 2. The study opened in December 2019 and is currently enrolling in the dose escalation phase. Clinical trial information: NCT04077021.

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

scholarly journals 523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
Elaine Shum ◽  
Matthew Reilley ◽  
Yana Najjar ◽  
Adil Daud ◽  
John Thompson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Objective Response ◽  
Checkpoint Blockade ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Tumor Types

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

A phase 2 study of prostate specific membrane antigen antibody drug conjugate (PSMA ADC) in patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC) following abiraterone and/or enzalutamide (abi/enz).

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 144-144 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Nicholas J. Vogelzang ◽  
Gurkamal S. Chatta ◽  
Mark T. Fleming ◽  
David C. Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Tumor Imaging ◽  
Phase 1 ◽  
Serum Markers ◽  
Electrolyte Imbalance ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Antibody Drug Conjugate ◽  
Phase 2 Trial

144 Background: PSMA is a validated target that is overexpressed selectively on prostate cancer cells. PSMA ADC is a fully human IgG1 antibody conjugated to the microtubule disrupting agent MMAE which binds to PSMA-positive cells, inducing cytotoxicity. A phase 1 study showed activity and tolerability at doses from 1.8-2.5 mg/kg. We have enrolled 119 mCRPC pts who progressed following abi/enz in a phase 2 trial of PSMA ADC. Methods: mCRPC pts (83 taxane experienced (TE) and 36 chemo-naïve (CN)) were administered PSMA ADC 2.5 or 2.3 mg/kg IV Q3 wk for up to 8 cycles. 95% of pts received prior abi and/or enz treatment. Safety, antitumor activity (including PSA, CTCs, and tumor imaging) and exploratory biomarkers were assessed. Results: In all treated pts, PSA declines of ≥30% and ≥50% were 30% and 14%, respectively (n=113); CTC counts showed a decline of ≥50% in 78% of pts and conversion from ≥5 to <5 cells/7.5 ml blood in 47% (n=77) at any time during the study. For 2.3 mg/kg pts (n=82), corresponding PSA declines were 35% and 17%; CTC declines of ≥50% were seen in 81% and conversions in 46% (n=54). For CN pts, PSA declines of ≥30% and ≥50% were 31% and 20% (n=35); CTC declines of ≥50% were seen in 89% and conversion in 53% (n=19). Radiologic response by RECIST in 31 pts with measurable target lesions: PR in 4 pts, SD in 19 pts, and PD in 8 pts. Efficacy responses were associated with: low neuroendocrine serum markers (low CgA, low NSE, and high PSA), high PSMA expression (CTCs or tumor tissue). The most common treatment-related AEs ≥CTCAE grade 3 were neutropenia (TE: 25%; CN: 22%), fatigue (20%; 8%), electrolyte imbalance (16%; 11%), anemia (10%; 8%), and neuropathy (8%; 8%). Grade 1-2 neuropathy occurred in 40% (TE) and 50% (CN) of pts. Two 2.5 mg/kg pts (n=34) and one 2.3 mg/kg pt (n=85) died of sepsis. 2.3 mg/kg was better tolerated than 2.5 mg/kg. Conclusions: PSMA ADC was active in abi/enz refractory mCRPC pts. Clinically significant AEs included neutropenia and neuropathy. CTC conversions/reductions, PSA declines, and radiologic evidence of antitumor activity were seen in CN as well as heavily pretreated pts. Clinical trial information: NCT01695044.

scholarly journals A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand

2021 ◽  
Vol 7 (33) ◽  
pp. eabi8193
Author(s):  
Sung Chang Lee ◽  
Jennifer S. Y. Ma ◽  
Min Soo Kim ◽  
Eduardo Laborda ◽  
Sei-Hyun Choi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bispecific Antibody ◽  
In Vitro Cytotoxicity ◽  
Unnatural Amino Acid ◽  
Castration Resistant Prostate Cancer ◽  
Single Chain ◽  
Improved Stability ◽  
And Function

Despite the development of next-generation antiandrogens, metastatic castration-resistant prostate cancer (mCRPC) remains incurable. Here, we describe a unique semisynthetic bispecific antibody that uses site-specific unnatural amino acid conjugation to combine the potency of a T cell–recruiting anti-CD3 antibody with the specificity of an imaging ligand (DUPA) for prostate-specific membrane antigen. This format enabled optimization of structure and function to produce a candidate (CCW702) with specific, potent in vitro cytotoxicity and improved stability compared with a bispecific single-chain variable fragment format. In vivo, CCW702 eliminated C4-2 xenografts with as few as three weekly subcutaneous doses and prevented growth of PCSD1 patient-derived xenograft tumors in mice. In cynomolgus monkeys, CCW702 was well tolerated up to 34.1 mg/kg per dose, with near-complete subcutaneous bioavailability and a PK profile supporting testing of a weekly dosing regimen in patients. CCW702 is being evaluated in a first in-human clinical trial for men with mCRPC who had progressed on prior therapies (NCT04077021).

Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 119-119 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Philip W. Kantoff ◽  
Anthony E. Mega ◽  
Nicholas J. Vogelzang ◽  
Joe Stephenson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Phase 1 ◽  
Human Antibody ◽  
Prostate Specific Membrane Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Antibody Drug Conjugate ◽  
Previously Treated ◽  
Dose Levels ◽  
Specific Membrane

119 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. We have completed a phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. Methods: Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics (PK), PSA, circulating tumor cells (CTC), clinical disease progression and immunogenicity to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Results: 52 subjects with mCRPC were dosed in nine dose levels. All subjects received prior docetaxel, 5 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. Peripheral neuropathy was reported by 7 subjects after repeated doses. Two were grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible liver function tests (LFTs) elevations. Antitumor activity was manifested as reductions either in PSA or CTCs at ≥ 1.8 mg/kg PSMA ADC in approximately 50% of patients. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure and no accumulation was observed. Conclusions: PSMA ADC in this study was generally well tolerated in doses up to 2.8 mg/kg every three weeks in subjects with mCRPC, previously treated with taxane. Antitumor activity was seen at higher dose levels. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose of PSMA ADC was determined to be 2.5 mg/kg. A phase 2 trial in taxane refractory mCRPC has been initiated. Clinical trial information: NCT01414283.

Safety of BXCL701, a small molecule inhibitor of dipeptidyl peptidases (DPP), with pembrolizumab, (pembro, anti-PD-1) monoclonal antibody, in men with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 140-140
Author(s):  
Rahul Raj Aggarwal ◽  
Dan Costin ◽  
Vincent J. O'Neill ◽  
Cedric R Burg ◽  
Diane I. Healey ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Small Molecule ◽  
Dose Escalation ◽  
Small Molecule Inhibitor ◽  
Fixed Dose ◽  
Phase 2 ◽  
Final Dose ◽  
Molecule Inhibitor ◽  
Dipeptidyl Peptidases

140 Background: BXCL701 (talabostat previously PT100) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP) specifically DPP4, DPP8 and DPP9, which trigger macrophage cell death via pyroptosis resulting in proinflammatory stimulation of the innate immunity pathway. BXCL701 also inhibits fibroblast activation protein (FAP) releasing the FAP-mediated block of T-cell migration into the tumor. Expression of PD-L1 correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor responses were observed when BXCL701 was used with checkpoint inhibition. Methods: A phase 1b, multicenter study was undertaken. Eligible patients (pts) had progressing mCRPC (PCWG3), at least 1 line of systemic therapy and ≤ 2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anti-cancer therapy, and an ECOG PS of ≤ 2. Pts received fixed dose pembro (200mg IV q21 days) with escalating doses of BXCL701 (0.4mg and 0.6mg PO QD days 1-14 of 21-day cycles) using a 3 X 3 design. The key endpoints were safety and identification of the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC) was also assessed. Results: 3 pts were treated at the initial dose level for at least 4 cycles. All pts remain on treatment. No DLT or SAEs were reported. Grade 3 treatment related adverse events (TRAE) were limited to thrombocytopenia with transfusion in 1 pt. The only TRAE reported in more than one pt was hypocalcemia (2 pts). Safety assessment of BXCL701+pembro is ongoing at the final dose escalation cohort. As DPP9 is amplified in approximately 17% of treatment associated small cell/neuroendocrine prostate cancer (tSCNC) compared to 5% or less in the broader prostate cancer population, the Phase 2 portion of this study will be limited to patients with evidence of t-SCNC or de novo SCNC, an aggressive phenotype with poor outcomes. Conclusions: BXCL701 0.4mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days is safe in pts with mCRPC. The final dose escalation supporting RP2D will be presented. Clinical trial information: NCT03910660.

TNB585.001: A multicenter, phase 1, open-label, dose-escalation and expansion study of tnb-585, a bispecific T-cell engager targeting PSMA in subjects with metastatic castrate resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5092-TPS5092
Author(s):  
Ben Buelow ◽  
Pranjali Dalvi ◽  
Kevin Dang ◽  
Ashwin Patel ◽  
Kiran Johal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Specific Antigen ◽  
Outpatient Basis ◽  
Open Label ◽  
Psma Pet ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

TPS5092 Background: Prostate cancer (CaP) is the most common cancer in US men. Disseminated CaP invariably progresses to metastatic castrate-resistant prostate cancer (mCRPC). Current treatment options for mCRPC usually lead to therapeutic resistance, and novel therapies are urgently needed. PSMA is a prostate-specific antigen over-expressed on most mCRPC. Antibodies against PSMA have been used to create T-cell engaging bispecific Abs (TCEs) and chimeric antigen receptor T cells, but all such approaches to date induce frequent/severe cytokine release syndrome (CRS). We combined a high-affinity αPSMA moiety with a low-activating αCD3 binder to create TNB-585; in preclinical studies, TNB-585 showed equivalent anti-tumor efficacy but much reduced cytokine secretion compared to PSMA-targeted TCEs with a strongly activating αCD3 domain. TNB-585 also has a full length silenced Fc domain, conferring a 3-week half-life. A phase 1 study investigating the safety, pharmacokinetics (PK), anti-drug antibodies (ADA) and preliminary activity of TNB-585 in patients with mCRPC is ongoing and described. Methods: TNB585.001 (NCT04740034) is an open-label, multi-center study of TNB-585 in patients with mCRPC. The study is divided into escalation (Arm A, N=24) and expansion (Arm B, N=30) arms. Subjects who have received 2 or more prior lines of therapy are eligible. Prior exposure to PSMA-targeted therapy is permitted, as are well-controlled HBV, HCV, and HIV infection; subjects with secondary malignancies that do not interfere with the study may also be enrolled. Other key inclusion/exclusion criteria include EGFR of > 30ml/min and ECOG ≤ 2. TNB-585 is administered as an intravenous infusion every 3 weeks. Subjects must be admitted for 48 hours after their 1st dose; TNB-585 is given on an outpatient basis thereafter. Dose escalation is proceeding in Arm A via single patient cohorts until the onset of toxicity or activity; thereafter subjects enroll using a BOIN design. Arm B will start once the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) has been selected. Subjects will be treated until progression or unacceptable toxicity. In Arm A, occurrence of dose limiting toxicities (DLTs) will drive identification of the MTD (or RP2D) based on the BOIN escalation and de-escalation boundaries (λe of 0.236 and a λd of 0.358). In Arm B accrual will be suspended if more than 33% of subjects experience a DLT event. Adverse events (AEs), laboratory profiles, and vital signs will be assessed throughout the study. AEs are graded according to the NCI CTCAE, version 5.0. The activity endpoints (per PCWG3/RECIST1.1) include overall response rate, PSA50, PSA30, CTC counts, progression free survival and overall survival. The relationship between PSMA expression (via PSMA-PET) and activity will be assessed. Clinical trial information: NCT04740034.

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