scholarly journals Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mamta Parikh ◽  
Chengfei Liu ◽  
Chun-Yi Wu ◽  
Christopher P. Evans ◽  
Marc Dall’Era ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Levels ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Phase Ib ◽  
Castration Resistant ◽  
Wide Range ◽  
Orally Bioavailable ◽  
Group 2

AbstractNiclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation has poor oral bioavailability. The primary objective of this phase Ib trial was to identify a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a novel reformulated orally-bioavailable niclosamide/PDMX1001 in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC). Eligible patients had progressing CRPC, adequate end-organ function, and no prior treatment with abiraterone or ketoconazole. Patients were treated with escalating doses of niclosamide/PDMX1001 and standard doses of abiraterone and prednisone. Peak and trough niclosamide plasma levels were measured. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and Prostate Cancer Working Group 2 criteria were used to evaluate toxicities and responses. Nine patients with metastatic CRPC were accrued, with no dose-limiting toxicities observed at all dose levels. The recommended Phase II dose of niclosamide/PDMX1001 was 1200 mg orally (PO) three times daily plus abiraterone 1000 mg PO once daily and prednisone 5 mg PO twice daily. Trough and peak niclosamide concentrations exceeded the therapeutic threshold of > 0.2 µM. The combination was well tolerated with most frequent adverse effects of diarrhea. Five out of eight evaluable patients achieved a PSA response; two achieved undetectable PSA and radiographic response. A novel niclosamide/PDMX1001 reformulation achieved targeted plasma levels when combined with abiraterone and prednisone, and was well tolerated. Further study of niclosamide/PDMX1001 with this combination is warranted.

A prospective phase I trial of dendritic cell-based cryoimmunotherapy in metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3029-3029
Author(s):  
Liv Cecilie Vestrheim Thomsen ◽  
Alfred Honoré ◽  
Lars Anders Reisæter ◽  
Bjarte Almås ◽  
Kristina Førde ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Dendritic Cell ◽  
Phase I ◽  
Checkpoint Inhibitors ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Total Cohort

3029 Background: Dendritic cell (DC)-based cryoimmunotherapy (CryoIT) was used to treat metastatic castration-resistant prostate cancer in a Phase I clinical trial. Primary objective was safety of treatment. Secondarily, clinical, radiological and immunological treatment responses were investigated. Methods: In 18 patients cryoablation by a freeze-thaw process under general anesthesia was performed, followed by intratumoral autologous immature DC injection. In the last 9 patients checkpoint inhibition of either CTLA-4 or PD-1 was added. Subjects had minimum 46 weeks follow-up. Adverse events (AEs) and blood analyses were registered at all visits. Disease progression was determined by three imaging modalities according to (i)RECISTv1.1 and progression-free survival (PFS) by Kaplan-Meier method. Circulating tumor cells (CTC/7.5 mL, CellSearch) and ultradeep T-cell receptor (TCR) b-chain sequences (TCRSafe) were enumerated. Patients were separated by CTC into none (n=10), 1-4 (n=4) and ≥ 5 (n=4). Health related quality of life (HRQoL) measured by EORTC-QLQ C30 questionnaire were answered at inclusion, and 10, 22 and 46 weeks post CryoIT. Scores were calculated according to the EORTC manual. Results: Subjects progressing within 22 weeks had higher PSA (p=0.03). AE profile of the total cohort (n=18) was comparable with interim reports (n=13); of 20 possible DC-related AEs one was severe (urinary retention) and 19 mild-to-moderate, and spread independent of treatment regime. Maximum tolerated dose of DC was not reached. By 46 weeks, imaging showed 6 patients partial response or stable disease. Median PFS was 150 days in total cohort. Pretreatment CTC counts ≥5 indicated higher progression rates and recurring CTC. Ultradeep TCR-sequencing showed more prevalent and higher expressed (>5-fold) new TCR clonotypes at 2-6 weeks in men without progression. Participants reported high and stable HRQoL scores throughout the study. However, presence of CTC was associated with worse HRQoL scores at week 10 (p=0.031) and 22 (p=0.005). Conclusions: DC treatment seems safe and well tolerated, also combined with checkpoint inhibitors. Effect is indicated in subjects with moderate pre-treatment PSA levels. Immune responses are suggested by higher number of novel TCR clonotypes in men with non-progressive disease. Clinical trial information: NCT02423928 .

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

Salvage chemotherapy with cisplatin, ifosfamide, and paclitaxel in metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 123-123
Author(s):  
Gunhild Von Amsberg ◽  
Mirjam Zilles ◽  
Philipp Gild ◽  
Winfried Alsdorf ◽  
Lukas Boeckelmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Synergistic Effects ◽  
Antagonistic Effect ◽  
University Hospital ◽  
Additive Effects ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Platinum Based Chemotherapy ◽  
Wide Range

123 Background: Recent developments in the treatment of metastatic castration resistant prostate cancer (mCRPC) lead to a revival of platinum-based chemotherapy demonstrating increased activity in patients with aggressive variants of disease. Here, we report on the results of a combinational salvage therapy with cisplatin, ifosfamide and paclitaxel (TIP) in mCRPC. Methods: We retrospectively analyzed patients with mCRPC treated with TIP at the University Hospital Hamburg-Eppendorf between November 2013 and September 2020. Accompanying in vitro analyses were performed using human prostate carcinoma cell lines harboring different levels of drug resistance including the docetaxel-resistant sublines PC3-DR and DU45-DR. Results: In total, 17 mCRPC patients treated with TIP were eligible for efficacy analyses with a median age of 65 yrs. At baseline, liver metastases were present in 88%, metastases of other visceral sides (lung, adrenal gland, brain) in 47% and bone metastases in 76% of the patients. Median hemoglobin was 9.8mg/dl, LDH 903 U/l and AP 205 U/l. Median PSA value was 77 ng/ml covering a wide range including three patients with a PSA-value below 1ng/ml. NSE was evaluated in 83% of the patients (median 38,5 U/l). Patients were extensively pretreated with a median of three treatment lines before TIP (100% docetaxel, 82% abirateron and/or enzalutamide, 47% cabazitaxel, 41% others). A median of 3,5 cycles of TIP were applied with 29% of the patients receiving the maximum of 6 cycles. Four patients discontinued treatment due to side effects (PNP, infection, ifosfamide induced psychosis). At interim analyses, 59 % of the patients showed a radiological response or stable disease with only one patient progressing till the end of treatment. Median PFS was 2.5 months, median OS 6 months. A decrease of PSA > 30% and LDH > 50% was observed in 41% and 35% of the patients, respectively. In vitro experiments revealed additive effects of TIP in 22Rv1, LNCaP and DU45 cells and synergistic effects in neuroendocrine LASCPC-01 cells. In PC3 cells, TIP induced antagonistic effects at lower doses, whereas dose-independent additive effects were observed in docetaxel-resistant PC3-DR. Surprisingly, preliminary data of combined therapies with different drug pairs suggest an antagonistic effect of paclitaxel in the combination with both, cisplatin and ifosfamide. Conclusions: Combinational therapy with cisplatin, ifosfamide and paclitaxel showed promising activity in some patients with aggressive mCRPC. Preclinical data suggest that the drug combination of cisplatin and ifosfamide rule the efficacy of TIP in mCRPC.

scholarly journals Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
pp. 1285-1301
Author(s):  
Andrew J. Armstrong ◽  
Jun Luo ◽  
David M. Nanus ◽  
Paraskevi Giannakakou ◽  
Russell Z. Szmulewitz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Messenger Rna ◽  
Specific Antigen ◽  
Hormonal Treatment ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Protein Assay ◽  
Castration Resistant ◽  
Low Probability ◽  
Taxane Chemotherapy

PURPOSE Androgen receptor splice variant 7 (AR-V7) detection in circulating tumor cells (CTCs) is associated with a low probability of response and short progression-free (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide or abiraterone. However, it is unclear whether such men benefit from taxane chemotherapy. PATIENTS AND METHODS PROPHECY is a multicenter prospective blinded study of patients with poor-risk mCRPC starting abiraterone or enzalutamide and observed through subsequent progression and taxane chemotherapy. We assessed AR-V7 status using the Johns Hopkins modified AdnaTest CTC AR-V7 messenger RNA assay and the Epic Sciences CTC nuclear-localized AR-V7 protein assay before treatment. The primary objective was to validate the independent prognostic value of CTC AR-V7 status based on radiographic/clinical PFS. OS, confirmed prostate-specific antigen (PSA), and objective radiologic responses were secondary end points. RESULTS We enrolled 118 men with mCRPC treated with abiraterone or enzalutamide, 51 of whom received subsequent docetaxel or cabazitaxel. Pretreatment CTC AR-V7 status by the Johns Hopkins and Epic Sciences assays was independently associated with worse PFS (hazard ratio [HR], 1.7; 95% CI, 1.0 to 2.9 and HR, 2.1; 95% CI, 1.0 to 4.4, respectively) and OS (HR, 3.3; 95% CI, 1.7 to 6.3 and HR, 3.0; 95% CI, 1.4 to 6.3, respectively) and a low probability of confirmed PSA responses, ranging from 0% to 11%, during treatment with abiraterone or enzalutamide. At progression, subsequent CTC AR-V7 detection was not associated with an inferior PSA or radiographic response or worse PFS or OS with subsequent taxane chemotherapy after adjusting for CellSearch CTC enumeration and clinical prognostic factors. CONCLUSION Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7–positive disease still experience clinical benefits from taxane chemotherapy.

Niclosamide in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC): initial results from a phase Ib/II trial.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 192-192 ◽  
Author(s):  
Chong-xian Pan ◽  
Primo Lara ◽  
Christopher P. Evans ◽  
Mamta Parikh ◽  
Marc Dall'era ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Serum Testosterone ◽  
Castration Resistant Prostate Cancer ◽  
Phase Ib ◽  
Serum Trough ◽  
Psa Response ◽  
Group 2 ◽  
Recommended Phase Ii Dose ◽  
Initial Results

192 Background: Prostate cancer is driven by androgen receptor (AR) signaling. The variant AR-V7 lacks the ligand binding domain, constitutively activates the AR pathway, and confers resistance to Abiraterone (Abi) and enzalutamide (Enza). We discovered that the anti-helminthic drug niclosamide targets AR-V7 and sensitizes resistant CRPC to Enza and Abi. We hypothesize that niclosamide/PDMX1001 potentiates the efficacy of Abi against CRPC. Here we report the initial results of this ongoing investigator-initiated phase Ib/II trial. Methods: Eligible patients (pts) have progressive CRPC with serum testosterone < 50 ng/dl. No prior Abi was allowed. In the Phase Ib cohort, pts received Abi 1000 mg PO qd, prednisone 5 mg PO bid, with intrapatient dose-escalation of niclosamide/PDMX1001 from 400 mg PO bid to 1600 mg PO tid. Trough niclosamide/PDMX1001 levels were measured. The Phase II cohort will enroll 27 patients with detectable AR-V7 in the peripheral blood. Co-primary endpoints include toxicity and response as determined by the Prostate Cancer Working Group 2 criteria. Results: Of 6 pts (age 74-83) in the Phase Ib cohort, five pts tolerated a niclosamide/PDMX1001 dose of 1,600 mg po tid without dose limiting toxicity; per protocol, this is the recommended Phase II dose. Niclosamide/PDMX1001 trough level was 0.305 and 0.496 µM in the two pts analyzed thus far, higher than the target level of 0.1µM required for anti-cancer activity. Of 6 pts, two pts achieved complete PSA response ( < 0.01 ng/ml), compared to historical control 0/30 pts treated with Abi alone; two with partial PSA response (≥50% decrease). Of the remaining two pts, one was prematurely taken off from the study after one cycle because of rising PSA, and the other had PSA decrease of 17.1%, but biopsy of the only enlarged lymph node showed all necrotic tissue. The only toxicity was Grade 1 nausea and diarrhea. The Phase II cohort will now enroll. Molecular correlative studies will be presented. Conclusions: The combination of niclosamide/PDMX1001, Abi and prednisone is well tolerated with promising safety and efficacy data. Targeted serum trough levels of niclosamide are clinically achievable. Clinical trial information: NCT02807805.

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