PACIFIC trial: A randomized phase II study of apatorsen and abiraterone in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) who have had PSA progression while receiving abiraterone (ABI).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 146-146 ◽  
Author(s):  
Kim N. Chi ◽  
Mark T. Fleming ◽  
Katherine Sunderland ◽  
Costantine Albany ◽  
Joel Gingerich ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Cancer Progression ◽  
Type I Error ◽  
Clinical Activity ◽  
Type I ◽  
Castration Resistant Prostate Cancer ◽  
Free Psa ◽  
Predictors Of Response ◽  
Ecog Ps

146 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 chaperones androgen receptor (AR) and enhances transactivation of AR-regulated genes. Apatorsen is a 2nd generation antisense that inhibits Hsp27 expression with clinical activity demonstrated in pts with mCRPC. Methods: mCRPC patients with PSA-only progression on ABI + prednisone (P) 10-20 mg daily were randomized to continuing ABI + P (Control Arm) or ABI + P with Apatorsen 600 mg IV x 3 loading doses then 800 mg IV weekly (Study Arm). Control Arm pts could cross over to receive apatorsen at time of progression. Primary endpoint was the proportion of pts progression free (PSA, clinical and radiologic) at day 60. Assuming a 25% increase in proportion of pts progression free and a null hypothesis of 5%, the planned sample size was 74 patients (type I error 20%, type II error 10%). Results: 72 pts were randomized: 36 to Control Arm, 36 to Study Arm. Baseline characteristics were similar in both arms: median age was 72 years (53-89); ECOG PS 0/1 in 44/56% of pts; median PSA of 29.4 (2.5-470.0); metastases to bone/lymph nodes/liver or lung occurred in 63/27/10%; elevated LDH and alkaline phosphatase in 26% and 26% ; 47% had ≥ 5 CTC/7.5 mL. Adverse events (AEs) were mainly grade 1-2 infusion reactions. 18 pts had grade 3/4 adverse events considered apatorsen related including: dyspnea (14%), fatigue (14%), increased ALT (9%), increased AST (9%), and thrombocytopenia (9%). Primary and secondary outcomes are summarized in the Table. Conclusions: Apatorsen may have activity when added to abiraterone for mCRPC patients progressing on abiraterone. Establishing predictors of response should be a priority for future studies. Clinical trial information: NCT01681433. [Table: see text]

A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4514-4514 ◽  
Author(s):  
Kim N. Chi ◽  
Sebastien J. Hotte ◽  
Susan Ellard ◽  
Joel Roger Gingerich ◽  
Anthony Michael Joshua ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Single Agent ◽  
Castration Resistant Prostate Cancer ◽  
Disease Response ◽  
Measurable Disease ◽  
The Difference ◽  
Ecog Ps

4514 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense oligonucleotide that inhibits Hsp27 expression with in vitro and in vivo efficacy and was well tolerated with single agent activity in phase I studies. Methods: Chemotherapy-naïve pts with no/minimal symptoms were randomized to receive OGX-427 600 mg IV x 3 loading doses then 1000 mg IV weekly with P 5 mg PO BID or P only. Primary endpoint was the proportion of pts progression free (PPF) at 12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) with 32 pts/arm provides 70% power to detect the difference at 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: 38 pts have been enrolled; 1st stage of accrual completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to OGX-427+P, 15 to P), baseline median age was 71 years (53-89), ECOG PS 0 or 1 in 66% and 34% of pts, median PSA 66 (6-606), metastases in bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P treatment, and 93% had ≥5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions (chills, diarrhea, flushing, nausea, vomiting) occurred in 47% of pts receiving OGX-427+P. One pt on OGX-427+P developed hemolytic uremic syndrome. A PSA decline of ≥50% occurred in 41% of pts on OGX-427+P, and 20% of pts treated with P. A measurable disease partial response was seen in 3/8 (38%) evaluable pts on OGX-427+P and 0/9 pts on P. CTC conversion from ≥5 to <5/7.5 ml occurred in 50% of pts on OGX-427+P and 31% treated with P. Thus far, in 26 evaluable pts the PPF at 12 weeks was 71% (95% CI: 42-92) in OGX-427+P treated pts and 33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical evidence for the role of Hsp27 as a therapeutic target in prostate cancer and support continued evaluation of OGX-427 for pts with CRPC. Funded by a grant from the Terry Fox Research Institute.

Pilot study of veliparib (ABT-888) with temozolomide (TMZ) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 224-224 ◽  
Author(s):  
Maha Hussain ◽  
Michael Anthony Carducci ◽  
Susan F. Slovin ◽  
Jeremy Paul Cetnar ◽  
Jiang Qian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Type I Error ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Type I ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Response ◽  
Clinically Significant

224 Background: Castration-resistant PC tumors exhibit increased PARP activity (critical enzymes for DNA damage repair). Veliparib is a novel, oral, potent inhibitor of PARP-1 and PARP-2. Preclinically, resistance to oral TMZ treatment in the PC3-Luc prostate cancer mouse model was reversed when mice were treated with veliparib. Based on the synergistic interaction, we evaluated the efficacy and safety of veliparib + TMZ in mCRPC pts. Methods: Eligible pts had mCRPC, PSA>2 ng/mL, progressed on at least one docetaxel based therapy and adequate organ function. Pts received veliparib 40 mg BID Days (D) 1-7 and TMZ D1-5 in 28D cycle (C) until disease progression (PD) or unacceptable toxicities. Tumor response was assessed every 8 weeks. Primary objective: Efficacy based on rate of PSA decline of 30% or greater. Secondary objectives: safety, RECIST objective response rate, progression-free survival (PFS), overall survival (OS) and biomarker analyses. A sample size of 25 pts provided 76% power to differentiate between PSA response rates of 5 and 20% at 1-sided type I error rate of 0.1. Results: 26 pts were enrolled; median age 67 years [55, 81]; median baseline PSA 107 ng/ml (6.9, 4584.4); 7/26 (27%) had 2 prior therapies. Median Cs of veliparib + TMZ received were 2 (range 1–9). Most frequent treatment related adverse events (AE) were fatigue (50%), nausea (38%) and constipation (23%). Grade 3/4 AEs in >10% of pts was thrombocytopenia (15%). All pts are off therapy. 25 pts were PSA response evaluable; 2 pts had a confirmed PSA response; 1 pt had a 37% decrease in PSA while the other pt had a 96% decrease in PSA and a 40% reduction in tumor size. 4/25 pts had stable disease for a minimum of 4 months (m). Median PFS was 2.1 m [95% CI: 1.8, 3.9]; 11/26 pts have died with median OS of 9.1 m [95% CI: 5.5, 11.7]. There was a negative correlation between change from baseline in circulating tumor cells and PFS. Conclusions: Veliparib + TMZ were well tolerated with evidence of some activity. Due to lack of activity of TMZ in CRPC,veliparib-induced potentiation of TMZ may not be clinically significant. Other combinations will be explored with higher doses of veliparib. Biomarker data will be presented.

A randomized phase II study of OGX-427 plus prednisone versus prednisone alone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 121-121 ◽  
Author(s):  
Kim N. Chi ◽  
Sebastien J. Hotte ◽  
Susan Ellard ◽  
Joel Roger Gingerich ◽  
Anthony Michael Joshua ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Single Agent ◽  
Prior Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Disease Response ◽  
The Difference ◽  
Ecog Ps

121 Background: Heat Shock Protein 27 (Hsp27) is a stress-activated, multi-functional chaperone protein highly expressed in cancer that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense that inhibits Hsp27 expression with in vitro and in vivo efficacy. Phase I studies have demonstrated tolerability and single agent activity. Methods: Patients (pts) with CRPC, no/minimal symptoms and any prior treatment other than chemotherapy were randomized 1:1 to receive prednisone (P) 5 mg PO BID or P with OGX-427 600 mg IV x 3 loading doses followed by 1000 mg IV weekly. Primary endpoint was the proportion of pts progression free (PSAWG 2 criteria) at 12 weeks. A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) will enrol 32 pts total per arm and provide 70% power to detect the difference at a 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: In the first 22 pts randomized (11 to OGX-427+P, 11 to P), baseline median age was 71 years (53-86), ECOG PS 0 or 1 in 64% and 36% of pts, median PSA 89 (6-606), metastases in bone/lymph nodes/liver or lung in 77%/64%/10%, 23% had prior treatment with P, and 91% had ≥5 CTC/7.5 ml (median 18/7.5 ml). Thus far, 82% of pts randomized to OGX-427+P have had a PSA decline (55% with ≥30% decline) and 18% a PSA increase; 40% of pts treated with P have had a PSA decline (20% with ≥30% decline), 10% no change and 50% with PSA increase. CTC conversion from ≥5 to <5/7.5 ml has occurred in 60% of pts randomized to OGX-427+P and 20% of pts treated with P alone. Grade 1-2 infusion reactions (e.g., chills, diarrhea, flushing) have occurred in 45% of pts receiving OGX-427+P and 1 pt developed hemolytic uremic syndrome after week 7 probably related to OGX. Conclusions: Preliminary data provide clinical support for the role of Hsp27 in AR signalling and as a therapeutic target for prostate cancer. Enrolment on this study continues. Funded by a grant from the Terry Fox Research Institute.

A phase II study of patupilone in patients (pts) with metastatic castration- resistant prostate cancer (CRPC) who have progressed after docetaxel

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5139-5139 ◽  
Author(s):  
E. K. Beardsley ◽  
F. Saad ◽  
B. Eigl ◽  
P. Venner ◽  
S. Hotte ◽  
...  
Keyword(s):  
Adverse Events ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Serious Adverse Events ◽  
Disease Response ◽  
Measurable Disease ◽  
Psa Response ◽  
Grade 3 ◽  
Ecog Ps

5139 Background: Chemotherapy for pts with CRPC who have progressed after docetaxel remains to be defined. Patupilone is an epothilone with broad spectrum pre-clinical activity including in taxane resistant models. Methods: Multicenter, 2-stage design. Pts with metastatic CRPC with progressive disease during or within 6 months of receiving docetaxel were eligible. Patupilone was initially given 10mg/m 2 IV every 3 weeks. PSA response rate (≥50% decline) was the primary endpoint (H0 = 15%, H1 = 25%, α = 0.1, β = 0.2). Secondary endpoints were measurable disease response, serial pain and analgesics scores, progression free survival (PFS) and overall survival (OS). Results: 83 pts were enrolled from March 2007-June 2008. 401 cycles administered (median 5, range 1–15). Baseline characteristics (range): median age 67 (47–85), PSA 212 (2.6–11520), hemoglobin 118 (89–160), median time to progression after docetaxel 1.0 months (0.0–6.0), number of prior chemotherapy regimens 1:2:3+ in 45:28:10 pts, ECOG PS 0–1:2 in 73:10 pts, disease in bone/lymph nodes/viscera in 76/47/14 pts respectively. In the first 6 pts, gastrointestinal serious adverse events (AE) occurred in 4 pts (diarrhea and vomiting) which lead to a dose reduction of patupilone to 8 mg/m2 for subsequent patients. Grade 3/4 related adverse events at this dose included fatigue (16%), diarrhea (13%) and anorexia (5%). There were no grade 3/4 hematologic AEs. In 78 pts evaluable for PSA response, PSA declines of ≥30% and ≥50% have occurred in 44/78 (56%) and 35/78 (45%) with a confirmed PSA response in 25 pts (32%). Partial response occurred in 5% and stable disease in 64% of 44 evaluable pts. Pain response (2 point decline on 6 point scale) occurred in 36 (51%) of 71 pts eligible for analysis. Median PFS for PSA and non-PSA outcomes (measurable disease/symptomatic progression or death) was 7.6 months (3.7–11.5) and 5.6 months (3.9–7.3) respectively. Follow up for OS is continuing. Conclusions: Patupilone 8 mg/m2 every 3 weeks was well tolerated and associated with encouraging PFS, PSA and pain responses in pts with docetaxel resistant/refractory disease. Further investigation of patupilone in this population is warranted. [Table: see text]

The Pacific trial: A randomized phase II study of OGX-427 in men with metastatic castration-resistant prostate cancer (mCRPC) and PSA progression while receiving abiraterone acetate (AA).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS5101-TPS5101
Author(s):  
Kim N. Chi ◽  
Christopher Sweeney ◽  
Cindy Jacobs ◽  
Patricia S. Stewart ◽  
Noah M. Hahn
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Cancer Progression ◽  
Performance Status ◽  
Clinical Activity ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Phase 2 Study ◽  
Psa Progression ◽  
To Receive

TPS5101 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression and over-expressed in many cancers including prostate, bladder, lung, and breast. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a second-generation antisense oligonucleotide designed to inhibit Hsp27 expression with in vitro and in vivo efficacy that increases apoptosis, inhibits tumor growth, sensitizes cells to chemotherapy and inhibits AR activity (Cancer Res 2007;67(21):10455). A phase 2 study of OGX-427 in patients with mCRPC reported preliminary activity with 50% of patients having a ≥50% PSA decline during treatment (J Clin Oncol 30, 2012 (suppl; abstr 4514)). The purpose of this study was to evaluate the clinical activity of OGX-427 in patients with mCRPC progressing on AA. Methods: In this randomized, phase 2 study, 74 evaluable patients with mCRPC who are currently receiving AA and have PSA progression despite a prior response are randomized 1:1 to receive either OGX-427 (600 mg IV x 3 loading doses in week 1 followed by 1000 mg IV weekly) with AA or continuing AA alone. Additional eligibility criteria include: ECOG performance status ≤1, no evidence of radiographic progression, adequate liver/kidney/bone marrow function, and ≤1 prior chemotherapy for CRPC. Protocol therapy is continued until disease progression, unacceptable toxicity, or patient withdrawal. Eligible control arm patients may cross over to receive OGX-427 following disease progression. The primary objective of the study is to evaluate the proportion of patients progression-free at Day 60 post randomization. Secondary objectives include comparisons between arms of PSA and disease response, progression free survival, time to disease progression, serial serum levels of Hsp27, and circulating tumor cell enumeration. The study is designed to detect a 25% improvement in the primary endpoint (α = 0.2, β = 0.1). The study was initiated December, 2012. Clinical trial information: NCT01681433.

scholarly journals Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 692
Author(s):  
Roosa Kaarijärvi ◽  
Heidi Kaljunen ◽  
Kirsi Ketola
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Treatment Resistance ◽  
Research Field ◽  
Phenotypic Change ◽  
Prostate Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Treatment Resistant ◽  
Molecular Features ◽  
Neuroendocrine Prostate Cancer

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.

scholarly journals TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3862
Author(s):  
Motasim Masood ◽  
Stefan Grimm ◽  
Mona El-Bahrawy ◽  
Ernesto Yagüe
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Transmembrane Protein ◽  
Intracellular Localization ◽  
Amyloid Β ◽  
Inverse Correlation ◽  
Response To Therapy ◽  
Endocrine Function ◽  
Type I ◽  
Amyloid Β Protein

Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Interestingly, through binding the amyloid β protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer’s disease. Despite undergoing extensive investigation over the last two decades, the primary literature regarding TMEFF2 is incoherent and offers conflicting information, in particular, the oncogenic vs. onco-suppressive role of TMEFF2 in prostate cancer. For the first time, we have compiled, contextualised and critically analysed the vast body of TMEFF2-related literature and answered the apparent discrepancies regarding its function, tissue expression, intracellular localization and oncogenic vs. onco-suppressive role.

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