Disulfiram (DSF) pharmacokinetics (PK) and copper PET imaging in a phase Ib study of intravenous (IV) copper loading with oral DSF for patients with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 96-96 ◽  
Author(s):  
Tian Zhang ◽  
Julie Kephart ◽  
Elizabeth Bronson ◽  
Monika Anand ◽  
Christine Daly ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Cell Lines ◽  
Peritoneal Metastases ◽  
Epithelial Cell Line ◽  
Castration Resistant Prostate Cancer ◽  
Phase Ib ◽  
Cytotoxicity Activity ◽  
Inactive Metabolite ◽  
Cu Uptake

96 Background: In preclinical models of prostate cancer (PC), DSF reduced tumor growth when co-administered with copper (Cu). Further, intracellular Cu uptake is partially regulated by androgen-receptor signaling. Given these data, we conducted a phase Ib clinical trial of mCRPC patients (pts) receiving Cu with DSF. Methods: Pts with mCRPC were assigned to 1 of 3 cohorts: neuroendocrine PC (NEPC) (A), adenocarcinoma (adenoCA) mCRPC with non-liver/peritoneal metastases (B), and adenoCA mCRPC with liver and/or peritoneal metastases (C). IV CuCl2 was given weekly for 3 doses with oral daily DSF. After CuCl2 dosing, daily oral Cu gluconate was started and DSF continued until disease progression as defined by Prostate Cancer Working Group Three (PCWG3). DSF and metabolite MeDDC levels in plasma were sampled at 0, 2, 4, 6 and 8 hours after the first dose and on Cycle 2 Day 1, and measured by HPLC. DSF and MeDDC were evaluated for cytotoxicity in 3 PC cell lines (22Rv1, LnCAP, and PC3) and a prostate epithelial cell line (PWR-1E). mCRPC Cu avidity was measured by 64Cu PET scan at baseline for all pts. Results: We treated 9 pts with mCRPC, 6 on cohort B and 3 on cohort C. No confirmed PSA declines or radiographic responses were observed in either cohort. Common adverse events included fatigue and psychomotor depression; no grade 4/5 AEs were observed. PK analysis: No DSF was detected in plasma (LOQ = 0.032 ng/mL, LOD = 0.01 ng/mL), whereas MeDDC was measurable in all study samples (LOQ = 0.512 ng/mL). MeDDC exhibited no cytotoxicity activity in PC cell lines. On 64Cu PET scans, bone metastases showed differential and heterogeneous Cu uptake. Lymph node and pulmonary metastases were evaluable, but not liver metastases due to significant Cu uptake in the liver. Conclusions: Oral DSF is not an effective treatment for mCRPC because it is quickly metabolized into the non-cytotoxic inactive metabolite, MeDDC. As such, this trial has stopped enrollment. Further work is needed to identify a stable DSF formulation so that the conditional lethality of Cu and DSF may be evaluated for treatment of mCRPC. Clinical trial information: NCT02963051.

A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS394-TPS394 ◽  
Author(s):  
Chong-xian Pan ◽  
Primo Lara ◽  
Christopher P. Evans ◽  
Mamta Parikh ◽  
Ralph de Vere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Response Rate ◽  
Performance Status ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Phase Ib ◽  
Androgen Synthesis ◽  
Psa Response

TPS394 Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.

scholarly journals 598P A phase Ib study of enzalutamide (Enza) plus CC-115 in men with metastatic castration-resistant prostate cancer (mCRPC)

2021 ◽  
Vol 32 ◽  
pp. S643-S644
Author(s):  
J.L. Zhao ◽  
E.S. Antonarakis ◽  
H. Cheng ◽  
D.J. George ◽  
R.R. Aggarwal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Phase Ib ◽  
Castration Resistant

scholarly journals A phase IB study of ABT-751 in combination with docetaxel in patients with advanced castration-resistant prostate cancer

2010 ◽  
Vol 21 (2) ◽  
pp. 305-311 ◽  
Author(s):  
J. Michels ◽  
S.L. Ellard ◽  
L. Le ◽  
C. Kollmannsberger ◽  
N. Murray ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Phase Ib ◽  
Castration Resistant

A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 125-125
Author(s):  
Vivek Narayan ◽  
Julie Barber-Rotenberg ◽  
Joseph Fraietta ◽  
Wei-Ting Hwang ◽  
Simon F. Lacey ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Cell Expansion ◽  
Castration Resistant Prostate Cancer ◽  
Car T Cells ◽  
Castration Resistant ◽  
Car T ◽  
Tumor Biopsies ◽  
Dose Dependent

125 Background: Prostate specific membrane antigen (PSMA) is a highly expressed tumor-associated antigen potentially amenable to chimeric antigen receptor-modified T (CAR-T) cell therapy for castration-resistant prostate cancer (CRPC). However, a primary challenge to the success of CAR-T therapy in CRPC is the immunosuppressive microenvironment, characterized by high levels of TGFβ. The immunosuppressive functions of TGFβ can be inhibited in T cells using a dominant negative TGFβ receptor (TGFβRdn), thereby enhancing antitumor immunity. Methods: We conducted a first-in-human phase 1 clinical trial to evaluate the feasibility, safety and preliminary efficacy of PSMA-directed/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in patients with metastatic CRPC (NCT03089203). In a 3+3 dose-escalation design, patients received a single dose of 1-3 x 107/m2 (Cohort 1) or 1-3 x 108/m2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting (LD) chemotherapy. In Cohort 3, one patient received 1-3 x 108/m2 CART-PSMA-TGFβRdn cells following a LD chemotherapy regimen of cyclophosphamide and fludarabine (Cy/Flu). In Cohort -3, three patients received 1-3 x 107/m2 CART-PSMA-TGFβRdn cells following Cy/Flu. Patients underwent metastatic tumor biopsies at baseline and on day 10 following treatment. Quantitative PCR of CART-PSMA-TGFβRdn DNA was performed at serial timepoints to evaluate for CAR-T expansion and persistence in peripheral blood and trafficking to target tissues. Multiplex cytokine analysis assessed CART-PSMA-TGFβRdn bioactivity. Results: Ten patients received CART-PSMA-TGFβRdn therapy across dose-level cohorts. All CART-PSMA-TGFβRdn infusion products met target transduction efficiency. Evaluation of CAR-T cellular kinetics demonstrated dose-dependent peripheral blood T cell expansion, as well as tumor tissue trafficking in post-treatment tumor biopsies. At Cohort 2 and above, 5 of 7 treated patients developed grade ≥2 cytokine release syndrome (CRS). Marked increases in inflammatory cytokines (IL-6, IL-15, IL-2, IFNγ) correlated with high-grade CRS events. One grade 5 adverse event (sepsis) occurred in Cohort 3. PSA decline was observed in 6 of 10 patients (median decline -33.2%, range -11.6% to -98.3%), and PSA30 response occurred in 4 of 10 patients (including one patient achieving PSA < 0.1 ng/mL). Conclusions: Adoptive cellular therapy with CART-PSMA-TGFβRdn is safe and feasible in patients with metastatic CRPC. A dose-dependent and lymphodepletion chemotherapy-dependent relationship was observed with CART-PSMA-TGFβRdn cell expansion, cytokine expression, CRS, and anti-tumor effect. Correlative cell trafficking and paired tumor Nanostring analyses will be presented. Future clinical investigations seek to enhance anti-tumor efficacy, while optimizing the therapeutic window. Clinical trial information: NCT03089203.

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