Phase II trial of single-agent ganetespib (STA-9090), a heat shock protein 90 (Hsp90) inhibitor in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) post docetaxel-based chemotherapy: Results of a Prostate Cancer Clinical Trials Consortium (PCCTC) study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5085-5085 ◽  
Author(s):  
Elisabeth I. Heath ◽  
Mark N. Stein ◽  
Ulka N. Vaishampayan ◽  
Emmanuel S. Antonarakis ◽  
Glenn Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Cancer Cells ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Stage 1

5085 Background: Hsp90 is a molecular chaperone required for the proper folding and activation of numerous client proteins and is critical to cell survival and proliferation. Ganetespib (G), a synthetic small molecule that binds to the ATP pocket in the N-terminus of Hsp90 causes the degradation of cellular proteins and ultimately death of cancer cells dependent on these proteins. G displays potent anticancer activity in prostate cancer cells. Methods: Eligible patients were ≥ 18 yrs old with ECOG performance status ≤ 2. Adequate hepatic, renal, and bone marrow function was required. Patients were treated with G 200 mg/m2 intravenously once weekly for 3 consecutive weeks followed by 1 off-week. The primary objective was to evaluate the 6-month progression-free survival (PFS). Secondary endpoints included overall safety and tolerability of G and overall survival. Exploratory markers including maspin, cytokeratins 8 and 18, and HDAC1 were obtained pre, during, and post G treatment. We sought ≥ 4 patients with ≥ 6 months PFS (a success) in Stage 1 of a 2-stage near-optimal Simon design. Results: 18 patients were enrolled at 4 institutions. The patients’ median age was 68 (range 51-82), 13 were Caucasian, 4 were African American, and 1 was Asian. Median PSA was 210.7 ng/mL (range 25.9 – 3,489 ng/mL). One patient never started therapy. Among the 17 treated patients, the median number of cycles was 2 (range 1-5). The most frequent Grade 3 toxicities were diarrhea (3 patients), fatigue (3), and dehydration (3). Prior therapy included abiraterone (8), sipuleucel-T (4), and other targeted therapy (4). With < 4 successes in Stage 1, the trial was terminated early. Median PFS was 1.9 months (90% CI: 1.7 – 2.7 months); median OS was 10.2 months (90% CI: 2.3 – 18.3 months). Exploratory markers have been evaluated and will be presented. Conclusions: Our study represents the first clinical trial of G in treating mCRPC patients. As a single agent therapy, G did not prolong PFS. Combination therapy is a consideration to improve therapeutic efficacy. Clinical trial information: NCT01270880.

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.

Abiraterone acetate (AA) with or without cabazitaxel (CBZ) in treatment of chemotherapy naive metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 84-84
Author(s):  
Susan F. Slovin ◽  
Karen E. Knudsen ◽  
Susan Halabi ◽  
Mark T. Fleming ◽  
Ana M. Molina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gene Networks ◽  
Radiographic Progression ◽  
Performance Status ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Castration Resistant

84 Background: Loss of retinoblastoma tumor suppressor (RB) function has been shown to lead to CRPC and is strongly associated with poor outcome. RB functions as a transcriptional repressor; as such, loss of RB causes de-repression of pro-tumorigenic gene networks, including deregulation of the androgen receptor (AR) locus, excessive AR production, and castration-resistant (ligand independent) AR activity that can bypass hormone therapy. Our hypothesis is that leveraging RB status can direct treatment decisions. The primary objective of the trial (NCT02218606) was to determine the radiographic progression free survival (rPFS) of AA/prednisone (AAP) with and without CBZ in mCRPC patients (pts) that have progressed on primary androgen deprivation therapy and no prior AR directed therapy or chemotherapy. Methods: This is a multicenter non-comparative randomized phase 2 trial. Pts were randomized 1:1 to AAP with crossover to CBZ upon AAP failure (Arm 1), or the combination of AAP + CBZ (Arm 2). Randomization was stratified by the CALGB 90401 prognostic risk groups. The primary endpoint was rPFS (time from randomization to radiographic progression or death, whichever occurs first). Arms were analyzed separately. Results: Between October 2014 and March 2019, 93 pts were accrued; 81 were randomized. Median age was 68 years and ECOG performance status was 0 or 1. Endpoints are shown in Table. Therapies were well tolerated. Conclusions: Results of AAP + CBZ (Arm 2) in chemotherapy naïve pts suggest that men may derive benefit from the earlier use of CBZ with acceptable toxicity, supporting further study of this combination in mCRPC pts. Circulating Tumor Cells are being analyzed for changes in RB/AR expression. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Sanofi US; Support: Prostate Cancer Foundation. Clinical trial information: NCT02218606. [Table: see text]

Olaparib (O) in patients (pts) with prostate cancer with BRCA1/2 inactivating mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5567-5567
Author(s):  
Evan P. Pisick ◽  
Elizabeth Garrett-Mayer ◽  
Susan Halabi ◽  
Pam K. Mangat ◽  
Eddy Shih-Hsin Yang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Ecog Performance Status ◽  
Grade 3 ◽  
Stage 1 ◽  
Anti Tumor Activity ◽  
Inactivating Mutations

5567 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Advanced prostate cancer (PC) pts with germline or somatic BRCA1/2 inactivating mutations treated with O are reported. Methods: Eligible pts had advanced PC, no remaining standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Tumor genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received O tablets or capsules dosed at 300 mg (n=24) or 400 mg (n=5), respectively, orally twice daily until disease progression. Simon 2-stage design tested the null disease control (DC) (objective response (OR) or stable disease at 16+ weeks (wks) (SD16+) according to RECIST) rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Pts had radiographic evaluations at 8 and 16 wks and then every 12 wks. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts with BRCA1/2 inactivating mutations were enrolled from Aug 2016 to Jul 2019; 4 were identified as ineligible after enrollment due to bone only disease and removed from analyses. Demographics and investigator-reported outcomes are summarized in the Table. Nine pts with OR and 8 with SD16+ were observed for DC and OR rates of 68% (90% CI: 53% - 77%) and 36% (95% CI: 18% - 57%), respectively. Six pts had at least one grade 3 AE or SAE at least possibly related to O including anemia, aspiration, dehydration, diabetic ketoacidosis, fatigue, and neutropenia. Conclusions: Monotherapy with O showed anti-tumor activity in heavily pre-treated PC pts with germline (1/2 pts with OR or SD16+) or somatic (16/23 pts with OR or SD16+) BRCA1/2 inactivating mutations. These findings extend results from recent trials of O in advanced prostate cancer pts with germline only BRCA1/2 mutations. Clinical trial information: NCT02693535 . [Table: see text]

A phase I study of TRC105 (anti-CD105 [endoglin] antibody) in metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 117-117 ◽  
Author(s):  
Fatima H Karzai ◽  
Andrea Borghese Apolo ◽  
David E. Adelberg ◽  
Ravi Amrit Madan ◽  
James L. Gulley ◽  
...  
Keyword(s):  
Response Rate ◽  
Vascular Endothelial Cells ◽  
Transmembrane Protein ◽  
Performance Status ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Endothelial Cell Proliferation ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status

117 Background: Preclinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Five cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10 or 15 mg/kg IV every 2 weeks (cohorts 1, 2, 3, and 5) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter. Results: Seventeen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Two patients remain on study (in cohort 5). Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.

Correlation of a novel whole blood RT-PCR assay measuring AR-V7 expression with outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate (ABI).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 223-223
Author(s):  
Tilman Todenhöfer ◽  
Arun Azad ◽  
Craig Stewart ◽  
Jian Gao ◽  
Bernhard J. Eigl ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Whole Blood ◽  
Performance Status ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Rt Pcr ◽  
Pcr Assay ◽  
Ecog Performance Status

223 Background: Expression of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has been associated with resistance to ABI and enzalutamide (ENZ) (Antonarakis et al. N Engl J Med 2014). We have developed a RT-PCR assay that is neither time sensitive nor requires CTC enrichment for detection of prostate cancer (PCa)-associated transcripts in whole blood. Using this assay, our aim was to correlate AR-V7 expression with outcomes on ABI. Methods: 2.5 ml whole blood was collected into PAXgene RNA tubes from mCRPC patients (pts) commencing ABI. RT-PCR was performed for the following genes: AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG. For each gene, the highest CT value among 20 normal controls was set as the threshold for a positive (+) test. Clinical endpoints were PSA50 response rate (RR) (PSA decline ≥ 50% confirmed ≥ 3 weeks later), PSA30 RR, time to PSA (PCWG2 criteria) or clinical progression (change in anti-cancer therapy or decline in ECOG performance status (PS) ≥ 2 levels due to PCa), and overall survival (OS). Results: Whole blood samples were obtained from 37 pts. Median age was 70. 59% received prior docetaxel. All pts were ABI and ENZ naïve. PSA50 RR was 37% and PSA30 RR was 48%. Median progression-free survival (PFS) was 3.8 months (mos) and median OS was 21.0 mos. 11% (4/37) of pts were AR-V7+. AR-V7+ pts were more likely to have high ALP (P= 0.04; Χ2), high LDH (P= 0.07) and ECOG PS ≥ 2 (P= 0.052). Pts with an AR-V7+ test had lower PSA50 RR (0% vs. 42%, P= 0.10; Χ2) and PSA30 RR (0% vs. 52%, P= 0.051) together with shorter median PFS (0.7 mos vs. 4.0 mos, P< 0.001; log-rank) and median OS (5.5 mos vs. 22.1 mos, P< 0.001). Other factors linked with worse OS were high ALP (P= 0.02), liver metastases (P= 0.03), ≤ 36 mos on primary hormone therapy (P= 0.04), HOXB13+ (P= 0.03) and KLK2+ (P< 0.001). Conclusions: RT-PCR detection of AR-V7 transcripts in whole blood was associated with a 0% PSA RR and significantly inferior PFS and OS in pts treated with ABI. These results reinforce the potential utility of AR-V7 as a prognostic and predictive biomarker for mCRPC. Validation of the assay in larger datasets is ongoing.

Phase Ib study of talimogene laherparepvec (T-VEC) injection into liver metastases (LMs) in combination with intravenous (IV) atezolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or colorectal cancer (CRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS725-TPS725
Author(s):  
J. Randolph Hecht ◽  
Arlene Chan ◽  
Miguel Martin ◽  
Nicolas Mach ◽  
Sara A. Hurvitz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Primary Objective ◽  
Intralesional Injection ◽  
Ecog Performance Status ◽  
Eligibility Criteria ◽  
The Usa

TPS725 Background: T-VEC is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immune responses. Atezolizumab is a monoclonal antibody checkpoint inhibitor (CPI) that targets PD-L1. The safety of intrahepatic administration of T-VEC has been demonstrated in a prior clinical trial (NCT02509507). A previous trial of T-VEC in combination with a CPI in advanced melanoma demonstrated improved responses compared to those with a CPI alone (Puzanov et al. JCO. 2016; 34:2619-26). We hypothesize that T-VEC combined with a CPI may also be effective in other tumor types. This phase 1b, multicenter study evaluates the safety of intrahepatic injection of T-VEC in combination with IV atezolizumab in pts with TNBC or CRC with LMs. Methods: The study will enroll up to 36 pts in two parallel cohorts (18 TNBC, 18 CRC) at sites in the USA, Europe, and Australia. The primary objective is to evaluate the incidence of dose-limiting toxicities (DLTs). Secondary objectives include objective response rate, lesion-level responses in injected and uninjected tumors, progression-free survival, and overall survival. Key eligibility criteria include age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG performance status 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable, injectable LM. T-VEC will be given by image-guided intralesional injection of up to 4 mL of 106 plaque forming units (PFU)/mL on day 1 and up to 4 mL of 108 PFU/mL every 21 days thereafter; atezolizumab 1,200 mg IV will be given on day 1 and every 21 days thereafter. The DLT-evaluation period is the first two cycles (1 cycle = 21 days). Interim safety analysis will occur after the first 4–6 pts have become DLT evaluable. Up to six cycles of T-VEC will be given with an additional 6 cycles allowed. After cycle three, nonhepatic lesions may be injected, subject to protocol-defined criteria. The study opened for enrollment in January 2018. (NCT03256344) Clinical trial information: NCT03256344.

Phase 1 expansion trial of the LSD1 inhibitor seclidemstat (SP-2577) with and without topotecan and cyclophosphamide (TC) in patients (pts) with relapsed or refractory Ewing sarcoma (ES) and select sarcomas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS11577-TPS11577
Author(s):  
Damon R. Reed ◽  
Sant P. Chawla ◽  
Bhuvana Setty ◽  
Leo Mascarenhas ◽  
Paul A. Meyers ◽  
...  
Keyword(s):  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
The United States ◽  
Primary Objective ◽  
Tumor Growth Inhibition ◽  
Ecog Performance Status

TPS11577 Background: Several sarcomas possess chromosomal translocations in FET family members ( FUS, EWSR1, and TAF15) responsible for cancer development. Sarcomas caused by FET family gene rearrangements include ES, desmoplastic round cell small tumors (DSRCT), myxoid liposarcoma (ML), and several others. Lysine specific demethylase 1 (LSD1) is a critical protein for sarcoma development and progression through its colocalization and/or association with several FET family oncogenic transcription factors. This suggests that pharmacologic inhibition of LSD1 may be a therapeutic strategy. Seclidemstat (SP-2577, Salarius Pharmaceuticals) is an oral, first-in-class, small molecule with reversible, noncompetitive inhibition of LSD1 (IC50: 25–50 nM). In vitro and in vivo data demonstrate seclidemstat, or analogs, modulate EWS/ETS transcriptional activity, down-regulating oncogene expression and up-regulating tumor-suppressor gene expression, leading to significant tumor growth inhibition in ES mouse xenograft studies. Seclidemstat has shown in in vitro ES cell lines near additivity efficacy when added to TC. In in vitro studies of other FET-translocated sarcomas, including ML (FUS/DDIT3 fusion) and clear cell sarcoma (EWS/ATF1 fusion), seclidemstat showed anti-proliferative activity. In an ongoing Phase 1 trial investigating single agent seclidemstat in advanced solid tumors (NCT03895684), three pts with metastatic FET-translocated sarcomas had a median progression-free survival of 5.7 months (range: 4.3–7.2) with a best response of stable disease despite having a median of 5 (range: 1–7) prior therapies. Methods: This dose expansion Phase 1 study (NCT03600649) assesses seclidemstat at 900 mg PO BID, the recommended Phase 2 dose, in two expansion cohorts: a single agent expansion in select sarcoma pts (n = 30) and a safety lead-in dose escalation and expansion (n = 24) of seclidemstat combined with TC in pts with ES. Pts must be ≥12 years old, have ECOG performance status of 0 or 1, with a life expectancy > 4 months. In the select sarcoma cohort, pts must have ML (n = 15) or other sarcomas with FET family translocations (n = 15) including DSRCT. One to 3 prior lines of therapy are allowed. In the ES combination cohort, up to 2 lines of prior therapy are allowed. Primary objective is safety/tolerability and secondary objective is efficacy. The trial is currently recruiting across 8 locations in the United States. Clinical trial information: NCT03600649.

A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic castration resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3043-3043
Author(s):  
Fatima H Karzai ◽  
Andrea Borghese Apolo ◽  
David Adelberg ◽  
Ravi A. Madan ◽  
James L. Gulley ◽  
...  
Keyword(s):  
Response Rate ◽  
Vascular Endothelial Cells ◽  
Transmembrane Protein ◽  
Performance Status ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Endothelial Cell Proliferation ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status

3043 Background: Pre−clinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Six cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10, 15, or 20 mg/kg IV every 2 weeks (cohorts 1, 2, 3, 5, and 6) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter. Results: Sixteen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. An additional cohort (6), with dosage of 20 mg/kg, is currently under investigation. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.

Radium-223 (Rad) and niraparib (Nira) treatment (tx) in castrate-resistant prostate cancer (CRPC) patients (pts) with and without prior chemotherapy (chemo).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5540-5540
Author(s):  
William Kevin Kelly ◽  
Benjamin Leiby ◽  
David Johnson Einstein ◽  
Russell Zelig Szmulewitz ◽  
A. Oliver Sartor ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Single Agent ◽  
Primary Objective ◽  
Dose Finding ◽  
Parp Inhibition ◽  
Clinical Activity ◽  
Ecog Performance Status ◽  
Radium 223 ◽  
Parp 1

5540 Background: Despite multimodality txs such as surgery, radiotherapy, hormonal tx and chemo, metastatic CRPC (mCRPC) prognosis remains poor. Research suggests PARP-1 is a key regulator of androgen receptor (AR) signaling and transition to lethal CRPC. Nira is a safe, potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in CRPC, and Rad is an alpha particle emitter. Addition of PARP inhibition may further enhance the clinical benefit of Rad. Nira has a favorable safety profile however, data on safety, tolerability and efficacy of Nira plus radiotherapy is limited. We hypothesize that targeting the PARP-1/AR axis in combination with radiation is safe and will improve mCRPC management. Methods: This is a phase (ph) Ib dose finding study (NCT03076203) of pts with progressive mCRPC using Time-to-Event Continual Reassessment Method (TITE-CRM). The primary objective is to determine the optimum ph II dose of Nira plus Rad (55 kBq/kg of body weight) in pts with and without prior chemo. Secondary endpoints include PSA reduction at 12 weeks (wks) and radiographic progression-free survival at 6 months. Pts enrolled to one of three dose levels of Nira (100, 200, and 300 mg PO daily). After completing 6 cycles of Rad, pts continued on Nira alone until objective progression, tx intolerance or pt decision. TITE-CRM identifies the maximum tolerated dose (MTD) based on toxicities observed over 12 wks of tx. Results: Between Oct 2017 and Jan 2020, 30 pts were enrolled (15 per stratum). Median age was 70 years; ECOG performance status was 0. The MTD of Nira was 100 mg in the chemo-exposed arm and 200 mg in the chemo-naïve arm. 19 Grade ≥ 3 adverse events were possibly related to tx: lymphocyte count decrease (n = 4, 13%), neutrophil count decrease (n = 3, 10%), anemia (n = 3, 10%), hypertension (n = 3, 10%), platelet count decrease (n = 2, 7%), creatinine increase (n = 1, 3%), hydronephrosis (n = 1, 3%), nausea (n = 1, 3%), white blood cell count decrease (n = 1, 3%). Tx duration and PSA response are shown in the table. Conclusions: Nira plus Rad was determined to be safe and tolerable. The MTD of Nira was identified and is pending ph II investigation. Managed by: Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Scientific Affairs and Bayer Healthcare Pharmaceuticals, Inc Clinical trial information: NCT03076203 . [Table: see text]

A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1003-1003 ◽  
Author(s):  
H. S. Rugo ◽  
A. Stopeck ◽  
A. A. Joy ◽  
S. Chan ◽  
S. Verma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Single Agent ◽  
Metastatic Breast ◽  
Primary Objective ◽  
Hazard Ratio ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Grade 3

1003 Background: Single-agent DOC is commonly used to treat MBC. Axitinib (AG) is a potent TKI of VEGFRs. A phase I lead-in study identified 80 mg/m2 q3wks of DOC in combination with 5 mg BID of AG as the recommended phase 2 dose. The primary objective was to determine whether the time to progression (TTP) of AG+DOC arm is superior to DOC+PL. Methods: Pts with no prior chemotherapy for MBC and =12 mos from adjuvant chemotherapy (aCT), measurable disease, ECOG performance status (PS) of 0–2, and no uncontrolled brain metastases were randomly assigned (2:1) to receive treatment with either DOC+AG or DOC+PL without prophylactic growth factor in cycle 1. Tumor measurements were performed q9wks. Pts were stratified according to estrogen receptor (ER) status, prior aCT and PS (0–1 or 2). Results: A total of 168 pts were randomized. 92 pts had received prior aCT, 27 of whom received a prior taxane. Treatment arms were well balanced for prior adjuvant and taxane therapy. A median of 7 cycles of AG+DOC (range: 1–18) and 7 cycles of DOC+PL (range: 1–23) were administered. The most common non-hematologic adverse events observed in the AG+DOC arm included diarrhea (60%), nausea (53%), alopecia (51%), fatigue (49%), stomatitis (44%) and vomiting (40%). Grade 3/4 adverse events that were increased with AG+DOC vs DOC included febrile neutropenia (16 vs 7%), fatigue (13 vs 5%), stomatitis (13 vs 2%), diarrhea (11 vs 0%) and hypertension (5 vs 2%). Other grade 3/4 hematologic toxicities were similar in both arms. The median TTP (by RECIST) was 8.2 mo with AG+DOC arm and 7 mo with DOC+PL arm with a hazard ratio of 0.73 (prespecified, one-sided p=0.052). The overall response rate (ORR) was 40% for AG+DOC arm and 23% for DOC+PL arm (p=0.038). In a hypothesis-generating subgroup analysis, the median TTP in patients receiving prior aCT was 9.0 mo with AG+DOC arm and 6.3 mo with DOC+PL arm with a hazard ratio of 0.54 (p=0.012). Within this stratum, ORR was 45% for AG+DOC arm and 13% for DOC+PL arm (p=0.003). Conclusions: The anti-angiogenic TKI AG combined with DOC (80 mg/m2 q3wks) as first line therapy for MBC has an acceptable safety profile and promising anti-tumor activity. No significant financial relationships to disclose.

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