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).

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]

Updated results of a phase I/II prospective dose escalation trial evaluating safety and efficacy of combination 177Lu PSMA 617 and idronoxil in men with mCRPC post androgen signalling inhibition and taxane chemotherapy (LuPIN trial).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5557-5557
Author(s):  
Louise Emmett ◽  
Sarennya Pathmanandavel ◽  
Megan Crumbaker ◽  
Christopher Rofe ◽  
Andrew On Wah Yam ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Nadh Oxidase ◽  
Standard Of Care ◽  
Pain Scores ◽  
Psma Pet ◽  
Pet Ct ◽  
Psa Response ◽  
Taxane Chemotherapy ◽  
End Stage

5557 Background: There is no established standard of care post cabazitaxel in men with mCRPC. Ongoing trials in 177LuPSMA-617 have demonstrated good efficacy and safety, but synergistic combinations may further improve treatment responses. Idronoxil (NOX66) inhibits external NADH oxidase type 2 with downstream pro-apoptotic actions including radio-sensitization. Herein we present updated results and an additional cohort of a prospective single arm phase I/II dose escalation/expansion trial of LuPSMA-617 and NOX66 in mCRPC. Methods: Men with progressive mCRPC post androgen signalling inhibition (ASI) and 2 lines of taxane chemotherapy were considered eligible. Key inclusion criteria included PSMA PET/CT intensity SUV max > 15 with no discordant disease on FDG PET/CT, Hb >10, Platelets >100 and GFR >40mls/min. Enrolled patients received up to 6 doses of 177 Lu-PSMA 617 (7.5Gbq) day 1 every 6 weeks in combination with NOX66 days 1-10 each cycle. Cohort 1 (n=8) received 400mg NOX66. Cohorts 2 and 3 subsequently received 800mg and 1200mg of NOX66, respectively, following safety reviews. Data regarding safety, efficacy, pain scores, and QOL were collected. Results: 32 men were enrolled in cohorts 1&2 (November 2017 – June 2019) and 24 in cohort 3 (August 2019-February 2020). To date there have been no dose-limiting toxicities. Data for cohort 3 are immature. For cohorts 1 & 2: 31/32 men received ≥2 cycles, with 12/32 (47%) completing 6 cycles. Any PSA response was seen in 84% (27/32), with a PSA response > 50% in 62.5% (20/32). Median PSA PFS is 6.1 months Of men with increased baseline pain scores ≥3 (24/32), 50% (12/24) had a clinically significant reduction in pain indicators. Adverse events are summarized below. Updated results for cohorts 1 and 2 and preliminary results of cohort 3 will be presented. Conclusions: Combination LuPSMA-617 + NOX 66 appears safe and efficacious in men with heavily pre-treated end stage mCRPC. Clinical trial information: ACTRN12618001073291 .

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.

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

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 25-25 ◽  
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]

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

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5028-5028 ◽  
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.

Final results of a phase I/II prospective dose escalation trial evaluating safety and efficacy of combination 177Lu PSMA 617 and NOX66 in men with end-stage metastatic castration-resistant prostate cancer (LuPIN trial).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 103-103
Author(s):  
Sarennya Pathmanandavel ◽  
Megan Crumbaker ◽  
Andrew On Wah Yam ◽  
Christopher Rofe ◽  
Bao Ho ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fdg Pet ◽  
Nadh Oxidase ◽  
Castration Resistant Prostate Cancer ◽  
Safety And Efficacy ◽  
Quantitative Pet ◽  
Pain Scores ◽  
Psma Pet ◽  
Pet Ct ◽  
Fdg Pet Ct

103 Background: 177LuPSMA – 617 is a promising therapy for metastatic castrate-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently and synergistic combination therapy may improve outcomes. We combined 177LuPSMA – 617 with idronoxil (NOX66), an inhibitor of external NADH oxidase type 2 with radio-sensitizing properties. We present the final safety and efficacy results. Methods: Men with progressive mCRPC after androgen signalling inhibition (ASI) and taxane chemotherapy were enrolled. Key inclusion criteria were: PSMA PET/CT intensity SUV max > 15 with no discordant disease on FDG PET/CT, haemoglobin > 100g/L, platelets > 100x109/L and eGFR > 40mls/min. Enrolled patients received up to six doses of 177 Lu-PSMA 617 (7.5Gbq) day 1 every 6 weeks in combination with NOX66 days 1-10 each cycle. Cohort 1 (n = 8) received 400mg NOX66. Following safety reviews the doses were escalated in cohorts 2 (n = 24) and 3 (n = 24) to 800mg and 1200mg of NOX66, respectively. Blood samples were prospectively collected for androgen receptor splice variant 7 (ARV7) expression. PSMA and FDG PET/CT were performed at study entry and on progression. The primary outcomes were safety and tolerability; the secondary outcomes evaluated were efficacy, pain scores, and quality of life. Results: Of the 56 men enrolled, all had received prior treatment with ASI and docetaxel, and 95% (53/56) had prior cabazitaxel. 96% (54/56) patients received ≥2 cycles and 46% (26/56) completed six cycles of treatment. Adverse events are summarized in the table below. PSA responses were as follows: 86% (48/56) had any PSA reduction and 61% (34/56) had > 50% PSA reduction. 84% (47/56) have had PSA progression to date with median follow up 18.9 months (95% CI 11.9-25.8). Median PSA PFS was 7.5 months (95% CI 6.0-9.0). 55% (31/56) have died and median overall survival was 19.7 months (95% CI 10.7-28.7). 34/56 men had baseline pain scores ≥3, of whom 53% (18/34) had significant reduction in pain indicators. There was no correlation between quantitative PET results and either PSA > 50% response, PSA PFS or OS. Conclusions: The combination of 177 Lu-PSMA 617 + NOX66 appears safe and efficacious in men with heavily pre-treated mCRPC. Exploratory analysis of ARV7 expression and quantitative PET imaging markers of treatment response and resistance is in progress. Clinical trial information: ACTRN12618001073291. [Table: see text]

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

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