Safety, efficacy, and pharmacodynamics of the investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase I/II study.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 98-98 ◽  
Author(s):  
David B. Agus ◽  
Walter Michael Stadler ◽  
Daniel H. Shevrin ◽  
Lowell Hart ◽  
Gary R. MacVicar ◽  
...  
Keyword(s):  
Phase 1 ◽  
Specific Antigen ◽  
Response Rates ◽  
Similar Efficacy ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Investigational Agent ◽  
Psa Response

98 Background: The investigational agent orteronel (TAK-700) is a selective 17,20 lyase inhibitor that down regulates androgenic steroid production in vitro and in vivo. Since phase 1 data in patients (pts) with mCRPC were promising, this open-label, multicenter study was expanded to gather additional data on safety and antitumor activity. Methods: The phase 2 portion of this study included four additional dose cohorts. Pts had no prior chemotherapy, and had baseline testosterone <50 ng/dL and prostate-specific antigen (PSA) ≥5 ng/mL. Results: 97 pts received orteronel 300 mg BID (n=23), 400 mg BID + prednisone 5 mg BID (n=24), 600 mg BID + prednisone (n=26), or 600 mg QD (n=24). At data cut-off (23 May 2011), 62% of pts had withdrawn (including 19% due to AEs and 19% for disease progression [PD]). Most common AEs were fatigue (76%), nausea (47%), and constipation (38%); most common grade ≥3 AEs were fatigue (12%) and hypokalaemia (8%). PSA response rates (≥50% decrease) at 12 wks were 63%, 50%, 41%, and 60% in the 300 mg BID, 400 and 600 mg BID + prednisone, and 600 mg QD groups. Of 51 RECIST-evaluable pts, 10 had partial responses (of which 5 confirmed), 22 stable disease, and 15 PD. At 12 wks, median testosterone decreased from baseline in all groups: (ng/dL, 12 wks/baseline) 0.98/8.50 (300 mg BID), 0.30/9.90 (400 mg BID +prednisone), 0.07/7.33 (600 mg BID + prednisone), 0.49/6.31 (600 mg QD). Similarly, at 12 wks, median dehydroepiandrosterone sulfate (DHEA-S) decreased from baseline in all groups: (µg/dL, 12 wks/baseline) 8.65/53.0 (300 mg BID), 0.10/36.3 (400 mg BID + prednisone), 0.10/51.7 (600 mg BID + prednisone), 5.30/31.5 (600 mg QD). Overall, mean circulating tumor cell numbers decreased from 16.6 (per 7.5mL blood) at baseline to 3.9 at 12 wks. Conclusions: Orteronel ≥300 mg BID appears active and well tolerated in pts with mCRPC, with similar efficacy ± prednisone. PSA response rates suggest that testosterone, rather than DHEA, may be a more reliable marker of lyase inhibition efficacy. Preclinical data and changes in pharmacodynamic parameters in this study suggest partially selective 17,20 lyase inhibition. Final data will be reported.

Results of a phase I study to evaluate the feasibility, safety, and biological effects of intravenous administration of wild-type reovirus with docetaxel to patients with advanced malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13524-e13524
Author(s):  
S. M. Rudman ◽  
C. Comins ◽  
D. Mukherji ◽  
M. Coffey ◽  
K. Mettinger ◽  
...  
Keyword(s):  
Phase I ◽  
Biological Effects ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Wild Type ◽  
Systemic Delivery ◽  
Open Label ◽  
Phase Ii Studies

e13524 Background: Reovirus has minimal pathogenicity in humans but selectively replicates in cells with activated Ras. Wild- type reovirus serotype 3 Dearing strain (Reolysin) has selective antitumor activity in vitro, in murine models, and after systemic delivery in humans in phase 1 trials. Synergistic tumour kill has been observed combining reovirus with taxanes in a range of cancer cell lines and in vivo. Methods: Patients were treated in an open-label, dose-escalating, phase I trial and received 3- weekly 75mg/m2 docetaxel i.v. and reovirus i.v. (day 1–5 of first week inclusive). Reovirus was administered at a starting dose of 3x109 tissue culture infectious dose (TCID50) and then increased to 1 x 1010 and 3 x 1010 TCID50. Primary endpoints were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and to recommend a dose and schedule for future investigation. Secondary endpoints were to evaluate pharmacokinetics, neutralizing antibody development, cell- mediated immune response and anti-tumour activity. Results: 17 patients were treated (15 males, median age 60 years). No MTD has been reached. DLT's observed were G4 neutropenia (and a recurrent perianal abcess) and G3 rise in AST. Other toxicities observed were fatigue, hypotension and neutropenic sepsis. At present, 5 patients remain on treatment. We have observed 2 partial responses (breast and gastric carcinoma) and 10 patients had stable disease as best response. Conclusions: Reovirus is well tolerated when administered in combination with intravenous docetaxel, with predictable toxicity observed. The recommended dose has been defined at 3x1010 TCID50 and phase II studies are planned. Objective radiological evidence of anticancer activity for this combination has been observed. [Table: see text]

An open label phase 1/2A study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TRC253, an androgen receptor antagonist, in patients with metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16542-e16542 ◽  
Author(s):  
Dana E. Rathkopf ◽  
Mansoor N. Saleh ◽  
Frank Yung-Chin Tsai ◽  
Mehmet Asim Bilen ◽  
Lee S. Rosen ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dose Escalation ◽  
Nuclear Translocation ◽  
Phase 1 ◽  
Specific Antigen ◽  
Xenograft Model ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Castration Resistant Prostate Cancer ◽  
Open Label

e16542 Background: TRC253 is a high-affinity, orally active small molecule antagonist of the androgen receptor (AR) and specific mutated variants of AR that does not possess agonist activity towards either wild type or mutated AR. TRC253 inhibits AR nuclear translocation as well as AR binding to DNA and is a transcription antagonist. TRC253 treatment is efficacious in an LNCaP xenograft model driven by F877L mutant AR. Methods: In P1 dose escalation, pts with mCRPC previously treated with an AR inhibitor were assigned to increasing TRC253 doses of 40-320 mg daily. Dose escalation followed single-pt dose escalation design for the 40, 80 mg cohorts and expanded to 3+3 design in the 160, 240, 280, and 320 mg cohorts to assess safety, determine the recommended phase 2 dose (RP2D), and evaluate prostate-specific antigen response at week 12. Toxicity and efficacy assessments used NCI-CTCAE v4.03 and PCWG3 criteria, respectively. Pts were centrally screened by circulating tumor DNA using the BEAMing digital PCR assay. Results: Twenty-two pts were enrolled in phase 1 at TRC253 doses of 40 (n = 1), 80 (n = 1), 160 (n = 2), 240 (n = 6), 280 (n = 4), and 320 mg (n = 8) daily in 28-day cycles. One DLT of G3 QTcF prolongation occurred at 320 mg. No drug-related SAEs were reported. Drug-related AEs ≥ G2 included QTcF prolongation (2 G2, 2 G3), elevated lipase (1 G3), fatigue (4 G2), arthralgia (1 G2), diarrhea (1 G2), and platelet count decrease (1 G2). One pt on study had AR F877L at baseline and remained on treatment for 49 wks with PR by RECIST. The remaining 21 pts did not have AR F877L at baseline and of these, 48% (10) remained on study > 6 cycles and one pts had a > 50% decrease in PSA. Target PK exposures were achieved consistently at 280 mg. 280 mg was selected as the RP2D based on safety and PK data. Conclusions: TRC253 daily at 280 mg was well-tolerated and selected as the RP2D. P2 dose expansion is currently enrolling 2 cohorts: 15 pts with AR F877L and 30 pts without AR F877L. The objectives of P2 include collection of additional data for safety, PK, PET and efficacy of TRC253 in mCRPC pts with specific AR mutations. Clinical trial information: NCT02987829.

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]

Ensituximab (E) in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results of a phase I/II clinical trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3081-3081 ◽  
Author(s):  
Richard D. Kim ◽  
Philip M. Arlen ◽  
Kwong Y. Tsang ◽  
Sharon Mavroukakis ◽  
Anjum Zaki ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Phase 1 ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Serum Cytokine ◽  
Open Label ◽  
Related Factors

3081 Background: E is an investigational, novel, chimeric monoclonal IgG1 antibody derived from an immunogenic neoantigen with sequence homology to MUC5AC that is preferentially expressed with exquisite specificity to pancreatic cancer and CRC. Its mechanism of action is via antibody-dependent cellular cytotoxicity (ADCC). The efficacy and safety of E was evaluated in a single-arm, open-label, phase 1/2 clinical trial of adult pts with refractory mCRC. Methods: Pts were selected based on > 20% expression of tumor antigen, as measured by immunohistochemistry. Based on phase 1 results, E was administered 3 mg/kg IV every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS). Serum cytokine levels were analyzed at baseline, day 4, and day 15. E-mediated ADCC of CD16 genotype V/V, V/F, and F/F pt PBMCs was measured with an IN-111 release assay using the E target-expressing ASPC-1 pancreatic cancer cell line. Results: Fifty-seven and 63 pts were evaluable for OS and safety, respectively. Median OS was significantly longer than historical control: 6.8 vs 5.0 months (mo); p = 0.007; 95% CI: 5.39,8.02. Three pts were alive at end of study (21, 21, and 24 mo); 21 pts survived ≥ 12 mo. Pts had a median of 4 prior therapies (range 2-9); 25% had received regorafenib. Forty-seven pts were evaluable by RECIST, and 20 (43%) had stable disease of target lesions at end of first course (day 57). E was well tolerated, with < 2% grade 3 and no grade 4 toxicities. There were no trends in serum cytokine and chemokine levels. Analysis of 56 samples (8 V/V, 26 V/F, 17 F/F, and 5 undetermined) showed that V/V PBMCs had significantly higher E-mediated ADCC than PBMCs harboring other genotypes. No correlation between CD16 polymorphism and pt outcome was observed. Conclusions: E demonstrated excellent tolerability and encouraging OS in this heavily pretreated population. Correlative in vitro data suggest that E can mediate higher levels of ADCC activity in individuals with a V/V versus other genotypes. The lack of correlation between CD16 polymorphism and pt outcomes in this study suggests that other immune-related factors (under investigation) may impact the efficacy of E in vivo. Clinical trial information: NCT01040000.

Pamiparib, an investigational PARP inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) and a circulating tumor cell (CTC) homologous recombination deficiency (HRD) phenotype or BRCA defects: A trial in progress.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5086-TPS5086 ◽  
Author(s):  
Simon Chowdhury ◽  
Joaquin Mateo ◽  
Mitchell Gross ◽  
Andrew J. Armstrong ◽  
Marcia Cruz-Correa ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Metastatic Disease ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Disease Status ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Measurable Disease ◽  
Psa Response

TPS5086 Background: Men with mCRPC who have a BRCA1/2 mutation ( BRCA1/2mut) or mutations in other genes resulting in HRD have a poor prognosis. A novel liquid biopsy test (EPIC Sciences) identifies CTCs with an HRD phenotype. Preliminary studies showed that these men may respond to treatment with a PARP inhibitor. Pamiparib, an investigational PARP1/2 inhibitor, has shown brain penetration and potent PARP–DNA complex trapping in nonclinical studies. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg orally twice daily (BID) was established as the recommended investigational dose. Methods: This open-label, global, phase 2 study (NCT03712930) evaluates the antitumor activity and safety/tolerability of pamiparib in mCRPC patients (pts) with CTC-HRD, assessed by the CTC-HRD assay, or deleterious germline/somatic mutations in BRCA1/2. Patients must have progressed on/after ≥1 androgen receptor-targeted therapy, received ≥1 taxane-based therapy, and have prostate-specific antigen (PSA) progression per PCWG3 criteria. Four cohorts of pts will receive pamiparib 60 mg BID in 28-day cycles. Cohort 1 will include ~50 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with measurable metastatic disease; Cohort 2 will include ~30 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with bone-only disease; Cohorts 3 & 4 will include ~20 pts with CTC-HRD-/unk + BRCA1/2mut mCRPC with measurable metastatic disease (Cohort 3), or bone-only disease (Cohort 4). Disease status will be assessed every 8 wks for 24 wks, then every 12 wks; PSA levels will be tested every 4 wks. Co-primary endpoints are radiographic ORR assessed by IRC (pts with measurable disease) and confirmed PSA response rate per PCWG3 criteria (pts +/- measurable disease). Secondary endpoints include ORR, time to PSA response/progression, duration of PSA response, time to symptomatic skeletal event, radiographic progression-free survival, overall survival, and safety. As of 05 December 2018, this study is actively enrolling. Clinical trial information: NCT03712930.

A phase II trial in progress: Pamiparib, an investigational PARP inhibitor, in patients with metastatic castration-resistant prostate cancer and a circulating tumor cell homologous recombination deficiency (HRD) phenotype or BRCA defects.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS328-TPS328
Author(s):  
Simon Chowdhury ◽  
Joaquin Mateo ◽  
Mitchell Gross ◽  
Andrew J. Armstrong ◽  
Marcia Cruz-Correa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Metastatic Disease ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Measurable Disease ◽  
Psa Response

TPS328 Background: Men with metastatic castration-resistant prostate cancer (mCRPC) who have a BRCA1/2 mutation ( BRCA1/2mut) or mutations in other HRD genes have a poor prognosis. The EPIC liquid biopsy test is a novel assay that can identify circulating tumor cells (CTC) with HRD associated phenotypes. Preliminary studies have shown that these men may respond to treatment with a PARP inhibitor. Pamiparib is an investigational PARP1/2 inhibitor that has shown brain penetration and potent PARP–DNA complex trapping in nonclinical studies. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg orally twice daily (BID) was established as the recommended investigational dose. Methods: This open-label, global, phase 2 study (NCT03712930) will evaluate antitumor activity and safety of pamiparib in mCRPC pts with CTC-HRD, assessed by the EPIC CTC-HRD assay, or deleterious germline/somatic BRCA1/2mut status. Patients must have progressed on/after ≥1 androgen receptor-targeted therapy, have received ≥1 taxane-based therapy, and have prostate-specific antigen (PSA) progression per PCWG3 criteria. Four cohorts of patients will receive pamiparib 60 mg BID in 28-day cycles. Cohort 1 will include ~50 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with measurable metastatic disease; Cohort 2 will include ~30 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with bone-only disease; Cohorts 3 & 4 will include ~20 pts with CTC-HRD-/unknown + BRCA1/2mut mCRPC with measurable metastatic disease (Cohort 3), or bone-only disease (Cohort 4). Disease status will be assessed every 8 wks for 24 wks, then every 12 wks; PSA levels will be tested every 4 wks. Co-primary endpoints are radiographic ORR assessed by IRC (pts with measurable disease) and confirmed PSA response rate per PCWG3 criteria (pts +/- measurable disease). Secondary endpoints include ORR, time to PSA response/progression, duration of PSA response, time to symptomatic skeletal event, radiographic progression-free survival, overall survival, and safety. Clinical trial information: NCT03712930.

scholarly journals KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhi Cao ◽  
Xiaolei Shi ◽  
Feng Tian ◽  
Yu Fang ◽  
Jason Boyang Wu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Biological Function ◽  
Malignant Tumors ◽  
Specific Antigen ◽  
Regulation Mechanism ◽  
Castration Resistant Prostate Cancer

AbstractLysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.

Preclinical and clinical pharmacology of EPI-7386, an androgen receptor N-terminal domain inhibitor for castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 119-119
Author(s):  
Ronan Le Moigne ◽  
Paul Pearson ◽  
Veronique Lauriault ◽  
Nan Hyung Hong ◽  
Peter Virsik ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Androgen Receptor ◽  
Phase 1 ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Pharmacokinetic Properties ◽  
Initial Cohort

119 Background: EPI-7386 is the newest of the “anitens”, a new class of compounds designed to inhibit androgen receptor activity by binding to the N-terminal domain (NTD) of the AR. Through this novel method of AR inhibition, anitens can block AR transcription even in the presence of AR ligand-binding domain (LBD) resistance mechanisms including point mutations and splice variants. Compared to the first generation aniten, EPI-506, which showed poor pharmacokinetic properties in patients, EPI-7386 is metabolically stable in vitro and in vivo. A Phase 1 clinical trial of EPI-7386 in metastatic castration-resistant prostate cancer patients failing standard of care therapies is ongoing and the pharmacokinetic properties of the drug in preclinical models as well as in the initial cohort of patients are presented. Methods: The metabolic stability of EPI-7386 was evaluated in vitro in mouse, rat, dog, monkey, and human hepatocytes. Projected PK parameters in humans were estimated from in vitro and in vivo clearance correlation (IVIVC). Induction of CYP isoforms was evaluated in human hepatocyte cultures. In patients, plasma concentrations of EPI-7386 were determined by LC-MS-MS, and 4-beta-hydroxycholesterol levels in plasma were followed over time as an indirect indicator of CYP3A induction. Results: In vitro hepatocyte studies demonstrated good metabolic stability for EPI-7386 with an in vitro half-life > 360 min. In animal PK studies, the terminal half-life of EPI-7386 was approximately 5.8 hours in mouse, 4.9 hours in rat, 13.4 hours in dog and the plasma clearance was low across species. The oral bioavailability of EPI-7386 ranged from 33–112% in mouse to > 100% in rat and dog. Using IVIVC, a predicted human clearance of 0.16–0.39 mL/min/kg was calculated for EPI-7386, which was in line with allometric scaling from animal PK parameters. Human PK profiles of different doses of EPI-7386 were simulated using predicted oral bioavailability, clearance, and volume of distribution. Cmax and AUC0–24h for the Phase 1 first-in-human study (NCT04421222) starting dose of 200 mg dose were predicted to be 6,915 ng/mL and 137,278 ng•h/mL respectively. A comparison between estimated PK parameters and actual values observed in the first patient cohort will be presented. Human hepatocyte CYP induction studies showed that EPI-7386 is not an inducer of CYP1A2 but may have the potential to induce CYP2B6 and CYP3A4. A comparison of 4-beta-hydroxy cholesterol levels measured during the phase 1 will be presented along with a comparison drawn from in vitro models. Conclusions: Pre-clinical characterization predicts that EPI-7386 has the appropriate PK and metabolic properties to afford exposure in patients at potentially efficacious levels following once-daily oral administration. PK measurements in the initial cohort of patients treated in the Phase 1 study will be presented. Clinical trial information: NCT04421222.

Phase Ib dose finding trial of intravenous panobinostat with docetaxel in patients with castration-resistant prostate cancer (CRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5064-5064
Author(s):  
D. E. Rathkopf ◽  
K. N. Chi ◽  
U. Vaishampayan ◽  
S. Hotte ◽  
N. Vogelzang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Dose Finding ◽  
Fixed Dose ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Ecog Performance Status ◽  
The Mean

5064 Background: Panobinostat (LBH589) is a potent pan-deacetylase inhibitor that has demonstrated activity in both in vivo and in vitro prostate cancer models. Methods: An open-label, multicenter, dose-finding trial of i.v. panobinostat given on Days 1 and 8 (10, 15, and 20 mg/m2) with fixed-dose docetaxel on Day 1 (75 mg/m2) and prednisone (5 mg bid) in a 21-day cycle is being conducted in chemotherapy-naïve patients (pts) with CRPC. All pts have adequate organ function and ECOG performance status (PS) < 1. Pts with significant cardiovascular abnormalities or QTcF >450 msec on screening ECG are excluded. This treatment is continued until disease progression or intolerability. The primary endpoint is determination of the maximum tolerated dose (MTD) of i.v. panobinostat in combination with docetaxel using the Bayesian logistic regression model. Dose-limiting toxicities (DLTs) are defined in first cycle. Results: Twenty-one pts (Cohort 1, n = 8; Cohort 2, n = 10; Cohort 3, n = 3) have been treated, with a median age of 66 yrs (range 50–88), median Gleason score of 9 (range 7–9), and median entry PSA of 67.1 (range 1.3–7920). DLTs include: Gr 4 bradycardia in Cohort 1 (n = 1) and Gr 4 neutropenia, resulting in Day 8 panobinostat dose omission (Cohort 2, n = 2; Cohort 3, n = 1). Gr 3/4 adverse events (AEs) include: neutropenia (n = 12), febrile neutropenia (n = 3), dizziness (n = 2), DVT (n = 1). Other Gr 1 or 2 AEs include: thrombocytopenia (n = 4), fatigue (n = 10), alopecia (n = 7), diarrhea, nausea, and rash (n = 5). Among the 599 ECGs, there was 1 QTcF increase of >60 ms from baseline and no QTcF >480 ms. Preliminary Cohort 1 pharmacokinetic (PK) data shows the mean panobinostat AUC0-inf does not differ between Day 1 (239 ng*hr/mL ) and Day 8 (254 ng*hr/mL), and the mean clearance value appeared to be similar between Days 1 and 8. In Cohort 1, the median number of cycles was 6. Four of 8 pts received >6 cycles. Five and four pts had >30% and >50% PSA reduction from baseline, respectively. In Cohort 2, 9 of 10 pts are still on treatment after 3 cycles. Conclusions: The combination of panobinostat at 10 or 15 mg/m2 with docetaxel is feasible and to date no PK interaction is apparent. Full safety, efficacy, and PK results will be presented. Under DOD PCCTC. [Table: see text]

An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with castrate-resistant prostate cancer (CRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5062-5062
Author(s):  
G. R. MacVicar ◽  
A. Greco ◽  
J. Reeves ◽  
J. Maleski ◽  
J. Holmlund ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Preliminary Evidence ◽  
Open Label ◽  
Serious Adverse Events ◽  
Vein Thrombosis

5062 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in CRPC and contribute to resistance to therapy. The oral pan-Bcl-2 inhibitor AT-101 (Bcl-2, Bcl-XL, Bcl-W, Mcl-1) is active as a single agent and in combination in in vitro and in vivo tumor models and as a single agent in CRPC. The Phase 1 portion of the study determined the recommended dose for phase II to be D (75mg/m2 q3weeks) in combination with P (5mg b.i.d. on days 1–21), and AT-101 at 40mg b.i.d. on days 1–3 of each 21-day cycle, and was previously reported. Methods: Men ≥18 years of age with chemotherapy-naïve CRPC (N = 36). Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: 36 patients (pts) have been enrolled in the study. Twenty-four (67%) pts achieved a partial response (PR) (>50% PSA decline), and 26 (72%) pts treated had at least a 30% decrease in PSA level. Nine of 19 pts (47%) with measurable disease had a PR. One PR was unconfirmed per RECIST. Thirteen pts (36%) completed >10 cycles of therapy (range 2–24) thus far. Four pts remains active. Safety data is available for 31 pts. The most common (>20%) Adverse Events (AEs) include: fatigue (68%), nausea (52%), diarrhea (45%), alopecia (32%), constipation and dysgeusia (26%), and neutropenia and vomiting (26%). Neutropenia was the only gr. 4 event occurring in more than one pt (3pts). Serious Adverse Events (SAEs) considered related were reported in 5 pts (16%). The only SAEs reported in 2 or more pts were urinary tract infection (3 pts) and deep vein thrombosis (2 pts) and none were considered related. No ileus has been reported. Conclusions: AT-101 when given in combination with D/P is well tolerated and shows preliminary evidence of efficacy in pts with CRPC. A randomized trial is ongoing. [Table: see text]

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