A phase I trial of weekly paclitaxel, 13- cis -retinoic acid, and interferon alpha in patients with prostate cancer and other advanced malignancies

Thalasila, Anu; Poplin, Elizabeth; Shih, Jhih-Yuan; Dvorzhinski, Dmitri; Capanna, Terry; Doyle-Lindrud, Susan; Beers, Stephanie; Goodin, Susan; Rubin, Eric H.; DiPaola, Robert S.

doi:10.1007/s00280-003-0644-6

Cited by 24 publications

(5 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The over-expression of Bcl-2 is implicated as a cause of hormonal and chemotherapy resistance and has been shown to increase with castration in prostate cancer [3,4]. Prior studies conducted by our group and other investigators demonstrated that retinoids can decrease expression of Bcl-2, that the combination of 13-cis retinoic acid (CRA) and interferon (IFN) enhanced the effect of paclitaxel chemotherapy, and that the combination can be safely administered in phase I studies [5-7]. More recently, our group and other investigators have studied novel BH3 domain mimetics such as AT101 and ABT263, which modulate multiple Bcl-2 family proteins, and are being tested in early clinical studies [8-10].…”

Section: Introductionmentioning

confidence: 99%

A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899

et al. 2010

View full text Add to dashboard Cite

BackgroundTo test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC).Methods70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC).ResultsThe PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03).ConclusionsTreatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy.Trial RegistrationClinical Trials Registration number: CDR0000067865

show abstract

Section: Introductionmentioning

confidence: 99%

A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Bcl-2 is an antiapoptotic protein that is overexpressed in multiple tumors including prostate cancer, thereby conferring resistance to therapies that induce apoptosis, such as ADT [3, 4]. Based upon preclinical data suggesting that the efficacy of ADT could be enhanced by combing ADT with AT-101, we undertook the current single arm phase II study in men with newly diagnosed hormone sensitive metastatic disease in order to determine if the combination could improve upon a novel clinical endpoint in this disease setting, the rate of patients achieving an undetectable PSA after 7 months of ADT and AT-101.…”

Section: Discussionmentioning

confidence: 99%

“…Prior studies in prostate cancer tissue demonstrated that Bcl-2 is over-expressed in most patients with castration-resistant prostate cancer (CRPC) [3, 4]. In animal models, Bcl-2 is responsible for drug resistance to chemotherapy and ADT, and modulation of Bcl-2 improves sensitivity [5, 6].…”

Section: Introductionmentioning

confidence: 99%

“…In animal models, Bcl-2 is responsible for drug resistance to chemotherapy and ADT, and modulation of Bcl-2 improves sensitivity [5, 6]. To date, several strategies have been employed to inhibit Bcl-2 including use of a clinical bcl-2 antisense or modulation of bcl-2 expression with the combination of interferon and cis-retinoic acid [3, 4, 7, 8]. AT-101 [R-(–)-gossypol acetic acid; Ascenta Therapeutics, Inc.] is an enantiomer of racemic gossypol, a natural substance found in cottonseeds.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Phase II Study of AT-101 to Overcome Bcl-2–Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer

Stein

Hussain

Stadler

et al. 2016

Clinical Genitourinary Cancer

Self Cite

View full text Add to dashboard Cite

Background We conducted a phase II study in men with castration sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer. Methods Patients with metastatic prostate cancer scheduled to start, or recently (within 6 weeks) initiated ADT, were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide started 6 weeks prior to initiation of oral AT-101, 20 mg/day for 21 days of 28-day cycle. The primary endpoint of the study was percentage of patients with undetectable PSA (less than or equal to 0.2) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between CHD1 and drug sensitivity, FISH with confocal microscopy was assessed in a subgroup of patients. Results Fifty-five patients enrolled, median age 61 years, median PSA of 27.6 ng/dL, and 72% had a Gleason score > 8. Three patients had visceral metastases and the remaining patients had bone or nodal metastasis. An undetectable PSA was achieved in 31% of patients. Twelve patients experienced serious adverse events (SAEs), and seven were considered related to study therapy. The majority of related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible with a non-significant association with therapeutic sensitivity in a small number of patients. Conclusion The combination of ADT and AT-101 did not meet the pre-specified level of activity for further development of this combination

show abstract

“…Regarding the use of cytokines in prostate cancer treatment, interferon-alpha is a cytokine that has been demonstrated to have antiproliferative effects against prostate cancer cells in vitro [ 160 ]. The combination of cis-retinoic acid and interferon-alpha has been explored as a potential treatment for prostate cancer [ 161 ]. In vitro studies have shown that interferon-alpha, with or without cis-retinoic acid, has antiproliferative effects against prostate cancer cell lines: prostate adenocarcinoma cell line 3 (PC3) and Daudi lymphoblastoid cell line-145 (D-145) [ 160 ].…”

Section: Other Immune-based Therapiesmentioning

confidence: 99%

Emerging Immunotherapy Approaches for Treating Prostate Cancer

Meng,

Yang,

Mortazavi

et al. 2023

IJMS

View full text Add to dashboard Cite

Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy has been limited in prostate cancer compared to other malignancies. This review summarizes key immunotherapy strategies under evaluation for prostate cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, chimeric antigen receptor (CAR) T cells, therapeutic vaccines, and cytokines. For each modality, the rationale stemming from preclinical studies is discussed along with outcomes from completed clinical trials and strategies to improve clinical efficacy that are being tested in ongoing clinical trials. Imperative endeavors include biomarker discovery for patient selection, deciphering resistance mechanisms, refining cellular therapies such as CAR T cells, and early-stage intervention were reviewed. These ongoing efforts instill optimism that immunotherapy may eventually deliver significant clinical benefits and expand treatment options for patients with advanced prostate cancer.

show abstract

A phase I trial of weekly paclitaxel, 13- cis -retinoic acid, and interferon alpha in patients with prostate cancer and other advanced malignancies

Abstract: This is the first study in which the safety and clinical activity of weekly TAX combined with CRA/IFN has been demonstrated. The assessment of PBMC bcl-2 is feasible in this weekly chemotherapy schedule

Cited by 24 publications

References 13 publications

A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899

A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899

A Phase II Study of AT-101 to Overcome Bcl-2–Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer

Emerging Immunotherapy Approaches for Treating Prostate Cancer

Contact Info

Product

Resources

About