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.

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.

Download Full-text

Ipilimumab (IPI) in metastatic castrate-resistant prostate cancer (mCRPC): Results from an open-label, multicenter phase I/II study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.25 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 25-25 ◽

Cited By ~ 8

Author(s):

Susan F. Slovin ◽

Omid Hamid ◽

Sheela Tejwani ◽

Celestia S. Higano ◽

Andrea Harzstark ◽

...

Keyword(s):

Phase 1 ◽

Specific Antigen ◽

Complete Response ◽

Open Label ◽

Response Table ◽

Common Grade ◽

Psa Response ◽

Castrate Resistant Prostate Cancer ◽

Grade 3 ◽

Castrate Resistant

25 Background: IPI is a fully human, anti-CTLA-4 monoclonal antibody capable of enhancing anti-tumor immunity. Preclinically, radiotherapy (XRT) and CTLA-4 blockade have synergistic anti-tumor activity. This phase 1/2 study in patients (pts) with mCRPC was designed to assess: safety of IPI at various doses, feasibility of combining IPI with XRT, and activity. Methods: mCRPC pts with or without prior chemotherapy were enrolled. In the dose-escalation phase, 33 pts (³6 pts per cohort) received IPI q3 weeks x 4 doses at 3, 5, or 10 mg/kg, or with XRT at 3 or 10 mg/kg. Single dose XRT (8 Gy/lesion, up to 3 lesions per pt) was given 24 to 48 h before the first IPI dose. The 10 mg/kg ± XRT cohorts were expanded to 50; 34 received IPI + XRT (Table). Based on clinical benefit, pts received additional doses of IPI. Endpoints were safety, and activity as assessed by serum prostate-specific antigen (PSA) and RECIST criteria. PSA was monitored monthly, with scans q3 months (mos). Results: There were no dose-limiting toxicities; 10 mg/kg ± XRT cohorts were, therefore, expanded for phase 2 evaluation. Treatment-related adverse events (AEs) and immune-related AEs (irAEs) were common across all cohorts with or without XRT. Common (≥ 15%) treatment-related AEs of any grade in the 10 mg/kg ± XRT group were fatigue (50%), diarrhea (54%), nausea (24%), colitis (22%), decreased appetite (22%), vomiting (18%), rash (32%) and pruritus (20%). Most common grade 3/4 irAEs were colitis (16%), diarrhea (8%) and hepatitis (10%). irAEs were generally responsive to immunosuppressives. Of 50 PSA-evaluable pts in the 10 mg/kg ± XRT group, 8 had PSA response (Table) lasting between 3 and 13+ mos. Of the 28 tumor-evaluable pts receiving 10 mg/kg ± XRT, 1 had complete response and 6 had stable disease. Conclusions: In pts with mCRPC, IPI 10 mg/kg alone or in combination with XRT showed clinical antitumor activity with disease control in some patients, and a generally manageable safety profile. The combination (IPI 10 mg/kg ± XRT) and monotherapy (IPI 10 mg/kg) are being explored in randomized phase 3 trials. [Table: see text]

Download Full-text

Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.7675 ◽

2012 ◽

Vol 30 (6) ◽

pp. 637-643 ◽

Cited By ~ 131

Author(s):

Eleni Efstathiou ◽

Mark Titus ◽

Dimitra Tsavachidou ◽

Vassiliki Tzelepi ◽

Sijin Wen ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Bone Marrow Aspirate ◽

Specific Antigen ◽

Abiraterone Acetate ◽

Open Label ◽

Clinical Observations ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

Tumor Expression

Purpose Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow–infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations. Patients and Methods This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues. Results Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression. Conclusion The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.

Download Full-text

A phase 1/1b multicenter, open-label, dose escalation and dose expansion study to evaluate the safety, pharmacokinetics, immunogenicity, and antitumor activity of MEDI3726 in patients with metastatic, castration-resistant prostate cancer who have received prior treatment with abiraterone or enzalutamide.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps5088 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS5088-TPS5088

Author(s):

Mark T. Fleming ◽

Richard Cathomas ◽

Daniel Peter Petrylak ◽

Judy Sing-Zan Wang ◽

Neil Harrison Bander ◽

...

Keyword(s):

Prostate Cancer ◽

Antitumor Activity ◽

Dose Escalation ◽

Phase 1 ◽

Specific Antigen ◽

Prior Treatment ◽

Castration Resistant Prostate Cancer ◽

Open Label ◽

Castration Resistant ◽

Label Dose

TPS5088 Background: Therapeutic advances have recently been achieved for patients with metastatic, castration-resistant prostate cancer (mCRPC) due to abiraterone acetate (ABI) and enzalutamide (ENZ). However, virtually all patients with mCRPC eventually progress in their disease, and further treatment options are limited. Prostate-specific membrane antigen (PSMA) is highly expressed in nearly all prostate cancers, and its expression is highest in mCRPC. MEDI3726 is an antibody-drug conjugate composed of anti-PSMA antibody derived from J591, site-specifically conjugated to the cytotoxic, DNA cross-linking, pyrrolobenzodiazepine dimer. MEDI3726 has demonstrated potent and specific in vitro and in vivo antitumor activity in human prostate cancer-derived preclinical models with different expression levels of PSMA. Methods: This is a first-in-human, phase 1/1b, multicenter, open-label, dose escalation and dose expansion study in patients who have received prior treatment with ABI or ENZ, with or without prior taxane-based chemotherapy in the mCRPC setting (NCT02991911). The primary objectives are to assess safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose or maximum administered dose of MEDI3726. The secondary objectives are to evaluate MEDI3726 for its antitumor activity (based on a composite response according to RECIST Version 1.1, a reduction in prostate-specific antigen level of 50% or more compared to baseline, or a conversion in the circulating tumor cell count [defined as a reduction from ≥5 cells/7.5 mL blood to < 5 cells/7.5 mL blood]), safety and tolerability in combination with ENZ, pharmacokinetics alone and in combination with ENZ, and immunogenicity. Recruitment is ongoing for this study, which has an estimated total target enrollment of 224 patients. Clinical trial information: NCT02991911.

Download Full-text

A phase Ib open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.tps391 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. TPS391-TPS391 ◽

Cited By ~ 2

Author(s):

Ulka N. Vaishampayan ◽

Vivek Narayan ◽

David Wise ◽

Joshua Michael Lang ◽

Benjamin H Lowentritt ◽

...

Keyword(s):

Prostate Cancer ◽

Dose Escalation ◽

Clinical Activity ◽

Open Label ◽

Prostate Cell ◽

Safety And Efficacy ◽

Phase Ib ◽

Label Dose ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

TPS391 Background: Metastatic castrate-resistant prostate cancer (mCRPC) remains an incurable illness as resistance develops after androgen deprivation therapy (ADT) and/or androgen receptor (AR) axis targeted therapies. The bromodomain (BRD) and extraterminal (BET) proteins are critical for transcription. Preclinically, one of these proteins, BRD4, acts in complex with AR to mediate androgen signaling that leads to prostate cell growth and proliferation. GSK525762 is an oral pan-BET inhibitor that suppresses BET dependent activated AR-driven transcription. Combined with androgen production or receptor targeted agents like abiraterone or enzalutamide, GSK525762 may enhance efficacy of or overcome resistance to either agent. Methods: This is a Phase Ib open-label, dose-escalation study to evaluate the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) in mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide. Patients must have documented prostate cancer progression as assessed by rising PSA or radiographic progression of soft tissue by PCWG3-modified RECIST 1.1 criteria or bone metastasis. Dose escalation is designed to identify safe doses to move into dose expansion. Dose expansion will explore safety and efficacy in patients who failed in first line (L2 population) or after multiple lines of prior therapy (LX population). Primary objectives include defining the safety, tolerability and clinical activity of GSK525762 when combined with products in Arm A or Arm B. Primary clinical activity endpoint is defined as the response rate of subjects achieving a 50% or more reduction from baseline of PSA at 12 weeks or thereafter. Dose escalation will employ a modified Toxicity Probability Interval (mTPI) design. Dose expansion will use a Bayesian adaptive design, which will calculate posterior probability that utility of the dose is clinically significant at interim futility analysis for each dose level. Funding: GSK Clinical trial information: NCT03150056.

Download Full-text

RESIST-PC phase 2 trial: 177Lu-PSMA-617 radionuclide therapy for metastatic castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5028 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5028-5028 ◽

Cited By ~ 3

Author(s):

Jeremie Calais ◽

Wolfgang P Fendler ◽

Matthias Eiber ◽

MIchael Lassmann ◽

Magnus Dahlbom ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Radionuclide Therapy ◽

Phase 2 ◽

Open Label ◽

Phase 2 Trial ◽

Psma Pet ◽

Psa Response ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

5028 Background: This is an investigator-initiated open-label prospective bi-centric single-arm phase 2 clinical trial (NCT03042312) of 177Lu-PSMA-617 radionuclide therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC). Methods: Patients with progressive mCRPC (biochemical, radiographic or clinical) after ≥1 novel androgen axis drug (NAAD), either chemotherapy (CTX) naïve or post-CTX, with sufficient bone marrow reserve and normal kidney function were eligible. All patients underwent a screening PSMA PET/CT to confirm target expression. Patients received up to 4 cycles of 177Lu-PSMA-617 every 8±1 weeks and were randomized into 2 treatment activities groups (6.0 or 7.4 GBq). Kidney dosimetry was performed for the first cycle. Efficacy was defined as serum PSA decline of ≥50% from baseline at 12 weeks and served as primary endpoint. Results: 64 patients (median PSA 75 ng/ml; range 0.5-2425) were included in the study. 20% were CTX naïve while 80% were post-CTX (1.9 CTX regimens on average, range 1-4). 45% completed 4 cycles of 177Lu-PSMA-617. Androgen deprivation therapy was given concomitantly in 83%, NAAD in 23% and immunotherapy in 6%. PSA decline of ≥50% was observed in 23% of patients at 12 weeks and in 38% of patients at any time (best PSA response). The median time to best PSA response was 22 weeks (range 6-49 weeks). 16% had a PSA decline of ≥90% and 59% had any PSA decline ( > 0%). Mild and transient (CTCAE grade 1-2) side effects included xerostomia (72%), nausea/vomiting (69%) and bowel movement disorders (45%). CTCAE grade 3 toxicity included nausea/vomiting (6%), anemia (8%), leukopenia (5%), kidney failure (3%), thrombocytopenia (3%), and neutropenia (3%). The mean kidney dose was 2.7 Gy for the first cycle (range 0.9-5.9) i.e. 0.4 Gy/GBq (range 0.15-0.9). There was no difference between the efficacy and toxicity for the 6.0 GBq (n = 23) and 7.4 GBq (n = 41) treatment arms. Conclusions: 177Lu-PSMA-617 radionuclide therapy is well tolerated in patients with progressive mCRPC. PSA declined by ≥50% in 38% of patients. The best PSA response rate occurred after 3 cycles. Updated data will be provided at the time of the conference. Clinical trial information: NCT03042312.

Download Full-text

Results of a phase I/II prospective dose-escalation trial evaluating safety and efficacy of combination 177LuPSMA-617 and NOX66 in men with mCRPC post androgen signalling inhibition and two lines of taxane chemotherapy (LuPIN trial).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.120 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 120-120

Author(s):

Louise Emmett ◽

Sarennya Pathmanandavel ◽

Andrew Nguyen ◽

Megan Crumbaker ◽

Andrew On Wah Yam ◽

...

Keyword(s):

Dose Escalation ◽

Nadh Oxidase ◽

Phase 1 ◽

Open Label ◽

Pain Scores ◽

Psma Pet ◽

Pet Ct ◽

Psa Response ◽

Castrate Resistant ◽

Taxane Chemotherapy

120 Background: Despite treatment advances, metastatic castrate resistant prostate cancer (mCRPC) remains a lethal disease. Trials in 177LuPSMA-617 have demonstrated good efficacy and safety, but synergistic combinations may further improve treatment responses. NOX66 inhibits external NADH oxidase type 2 with downstream pro-apoptotic actions including radio-sensitization. We present results of a prospective open label single arm phase 1/2 dose escalation/expansion trial of 177LuPSMA-617 and NOX66 in mCRPC. Methods: Men with progressive mCRPC post androgen signalling inhibition (ASI) and taxane chemotherapy were eligible. Inclusion criteria included PSMA PET/CT intensity > SUV max 15, with no discordant disease on FDG PET/CT, Hb > 100 g/L, Platelets > 90 x 106/L and GFR > 40 mL/min. Protocol allowed up to 6 doses of 177 Lu-PSMA 617 (7.5Gbq) on day 1 with NOX66 (suppository) given day 1-10 at 6-weekly intervals; the first 8 men received 400mg NOX66. After safety review, dose was escalated to 800mg. Data regarding safety, efficacy, pain scores, and QOL were collected. Results: 32/43 (26% imaging screen failures) screened men were enrolled (November 2017 – June 2019), of whom 100% had prior docetaxel and ASI, and 94% (30/32) cabazitaxel. All men received ≥ 2 cycles, with 12/32 completing 6 cycles, and 16/32 2 - 5 cycles, while 4/32 remain on treatment. Any PSA response was seen in 84% (27/32), with a PSA response > 50% in 62.5% (20/32). Median PSA PFS was 6.5 months (95%CI 3.54-9.3). To date, 72% (23/32) of patients have progressed. 34% (11/32) men have died with median OS not reached. 50% (12/24) of men with baseline pain scores ≥3 (24/32) had significant reduction in pain. Adverse events are summarized below. Conclusions: Combination 177LuPSMA-617 with NOX66 appears safe and efficacious in men with heavily pre-treated mCRPC. Clinical trial information: ACTRN12618001073291. [Table: see text]

Download Full-text