scholarly journals Angiogenesis Inhibitors in Personalized Combination Regimens for the Treatment of Advanced Refractory Cancers

2021 ◽  
Vol 1 ◽  
Author(s):  
Timothy Crook ◽  
Darshana Patil ◽  
Rajnish Nagarkar ◽  
Andrew Gaya ◽  
Nicholas Plowman ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Objective Response ◽  
Progression Free Survival ◽  
Angiogenesis Inhibitors ◽  
Cytotoxic Agents ◽  
Patient Specific ◽  
Solid Organ ◽  
Specific Combination ◽  
Anticancer Treatment ◽  
Combination Regimens

Background: Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with AGI and other anticancer agents when selected based on multi-analyte tumor interrogation (ETA: Encyclopedic Tumor Analysis) can expand the scope of AGIs in advanced refractory solid organ cancers with improved treatment responses.Methods: We evaluated treatment outcomes in 60 patients with advanced, refractory solid organ cancers who received ETA-guided combination regimens of AGI with other targeted, endocrine or cytotoxic agents. Radiological evaluation of treatment response was followed by determination of Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS).Results: Among the 60 patients, Partial Response (PR) was observed in 28 cases (46.7%), Stable Disease (SD) was observed in 29 cases (48.3%) and Disease Progression (PD, within 60 days) was observed in 3 cases (5.0%). The ORR was 46.7% and DCR was 95.0%. At the most recent follow-up the median PFS (mPFS) was 5.0 months and median OS (mOS) was 8.9 months. There were no Grade 4 therapy related adverse events or treatment related deaths.Conclusion: ETA-guided patient-specific combination regimens with AGI and other anti-neoplastic agents, can yield improved outcomes over AGI monotherapy. Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011,808. LIQUID IMPACT ID CTRI/2019/02/017,548.

scholarly journals Angiogenesis Inhibitors in Personalized Combination Regimens for the Treatment of Advanced Refractory Cancers

2021 ◽  
Author(s):  
Timothy Crook ◽  
Darshana Patil ◽  
Rajnish Nagarkar ◽  
Andrew Gaya ◽  
Nicholas Plowman ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Objective Response ◽  
Progression Free Survival ◽  
Angiogenesis Inhibitors ◽  
Cytotoxic Agents ◽  
Patient Specific ◽  
Solid Organ ◽  
Specific Combination ◽  
Anticancer Treatment ◽  
Combination Regimens

Abstract Background Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with AGI and other anticancer agents when selected based on multi-analyte tumor interrogation (ETA: Encyclopedic Tumor Analysis) can expand the scope of AGIs in advanced refractory solid organ cancers with improved treatment responses. Methods We evaluated treatment outcomes in 60 patients with advanced, refractory solid organ cancers who received ETA-guided combination regimens of AGI with other targeted, endocrine or cytotoxic agents. Radiological evaluation of treatment response was followed by determination of Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Results Among the 60 patients, Partial Response (PR) was observed in 28 cases (46.7%), Stable Disease (SD) was observed in 29 cases (48.3%) and Disease Progression (PD, within 60 days) was observed in 3 cases (5.0%). The ORR was 46.7% and DCR was 95.0%. At the most recent follow, up the median PFS (mPFS) was 5.0 months and median OS (mOS) was 8.9 months. There were no Grade 4 therapy related adverse events or treatment related deaths. Conclusions ETA-guided patient-specific combination regimens with AGI and other anti-neoplastic agents, can yield improved outcomes over AGI monotherapy. Trial Registration Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. LIQUID IMPACT ID CTRI/2019/02/017548.

scholarly journals Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
Timothy Crook ◽  
Darshana Patil ◽  
Andrew Gaya ◽  
Nicholas Plowman ◽  
Sewanti Limaye ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Outcomes ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Patient Specific ◽  
Solid Organ ◽  
Free Survival ◽  
Combination Regimens

Background: Activation of the mTOR signaling pathway is ubiquitous in cancers and a favourable therapeutic target. However, presently approved mTOR inhibitor monotherapies have modest benefits in labeled indications while poor outcomes have been reported for mTOR inhibitor monotherapy when administered in a label-agnostic setting based on univariate molecular indications. The present study aimed to determine whether patient-specific combination regimens with mTOR inhibitors and other anticancer agents selected based on multi-analyte molecular and functional tumor interrogation (ETA: Encyclopedic Tumor Analysis) yields significant treatment response and survival benefits in advanced or refractory solid organ cancers.Methods: We evaluated treatment outcomes in 49 patients diagnosed with unresectable or metastatic solid organ cancers, of whom 3 were therapy naïve and 46 were pre-treated in whom the cancer had progressed on 2 or more prior systemic lines. All patients received mTOR inhibitor in combination with other targeted, endocrine or cytotoxic agents as guided by ETA. Patients were followed-up to determine Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS).Results: The Objective Response Rate (ORR) was 57.1%, the disease Control rate (DCR) was 91.8%, median Progression Free Survival (mPFS) was 4.9 months and median Overall Survival (mOS) was 9.4 months. There were no Grade IV treatment related adverse events (AEs) or any treatment related deaths.Conclusion: Patient-specific combination regimens with mTOR inhibition and other anti-neoplastic agents, when selected based on multi-analyte molecular and functional profiling of the tumor can yield meaningful outcomes in advanced or refractory solid organ cancers.Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. ACTPRO ID CTRI/2018/05/014178. LIQUID IMPACT ID CTRI/2019/02/017548.

Multi-analyte interrogation based treatment of advanced refractory cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15624-e15624
Author(s):  
Dadasaheb B Akolkar ◽  
Timothy Crook ◽  
Darshana Patil ◽  
Anantbhushan Ranade ◽  
Amit Bhatt ◽  
...  
Keyword(s):  
Treatment Options ◽  
Objective Response ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Response To Treatment ◽  
Patient Specific ◽  
Solid Organ ◽  
Systemic Treatments

e15624 Background: Treatment of advanced refractory cancers face challenges in non-availability of systemic therapy regimens with evidenced benefit. Post failure of two to three lines of systemic treatments, patients with such cancers are usually considered for palliation or clinical trials. Prior attempts at label-agnostic treatment regimens (precision medicine) in such populations were largely based on a single-indication-single-drug paradigm which had limited application. We hypothesized that advanced refractory malignancies have latent vulnerabilities which can be identified by an integrational multi-analyte interrogation of the tumor, and can be targeted using patient-specific combination regimens to yield clinical benefit. Methods: Fresh tumor tissue and blood samples were obtained from 158 patients with solid organ cancers where the disease had progressed following failure of at least two lines of standard of care systemic treatment options. These samples were used for Encyclopedic Tumor Analysis (ETA) which interrogated gene mutations, gene overexpression, pathway dysregulation, immunohistochemistry as well as in vitro chemosensitivity profiling of viable tumor cells. Integration of datasets from the multi-analyte ETA was used to generate patient-specific therapy recommendations. Patients who received ETA-guided treatments were followed up and response to treatment was retrospectively evaluated from radiological scans. Results: All patients received ETA-guided individualized treatments which were combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Complete or Partial Response (CR or PR) was observed in 76 patients yielding an Objective Response Rate (ORR) of 48.1%. 67 patients showed Stable Disease (SD), thus yielding a Disease Control Rate (DCR) of 90.5%. Median Progression Free Survival (PFS) was 117 days (Range 27 – 379 days). There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: Viable efficacious combination treatment options can be made available for patients with advanced refractory malignancies via ETA, despite perceived non-availability or non-viability of standard of care treatment options.

Salvage immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combination therapy for metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16567-e16567
Author(s):  
Anish B. Parikh ◽  
Sarah P. Psutka ◽  
Yuanquan Yang ◽  
Katharine Collier ◽  
Abdul Miah ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Immune Checkpoint Inhibitor ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Free Survival ◽  
Kaplan Meier ◽  
Grade 3 ◽  
Combination Regimens

e16567 Background: ICI/TKI combinations are a new standard of care for the initial treatment (tx) of mRCC. Efficacy and toxicity of such combination regimens beyond the first-line (1L) setting remain unknown. Methods: We retrospectively reviewed charts for adult patients (pts) receiving an ICI/TKI combination in any line of tx for mRCC of any histology at one of two academic centers as of May 1, 2020. ICIs included pembrolizumab (Pm), nivolumab (Ni), ipilimumab (Ip), or avelumab (Av); TKIs included sunitinib (Su), axitinib (Ax), pazopanib (Pz), lenvatinib (Ln), or cabozantinib (Ca). Clinical data including pt demographics, histology, International mRCC Database Consortium (IMDC) risk group, tx history, and ICI/TKI tx and toxicity details were recorded. Outcomes included objective response rate (ORR), median progression-free survival (mPFS), and safety, analyzed via descriptive statistics and the Kaplan-Meier method. Results: Of 85 pts, 69 (81%) were male and 67 (79%) had clear cell histology. IMDC risk was favorable (24%), intermediate (54%), poor (20%), and unknown (2%). 39% had ICI/TKI tx in the 1L setting. ICI/TKI regimens included Pm/Ax (33%), Ni/Ca (25%), Ni/Ax (20%), Av/Ax (11%), Ni/Ip/Ca (8%), Ni/Su (2%), and Ni/Ln (1%). ORR and mPFS stratified by line of tx and prior tx are shown in the table. Of 52 pts who received ICI/TKI tx as salvage (after 1L), 52% had a grade 3 or higher (≥G3) adverse event (AE), of which the most common were anorexia (13.5%), diarrhea and hypertension (11.5% each), and fatigue (9.6%). 65% of pts on salvage ICI/TKI tx stopped tx for progression/death, while 16% stopped tx for ≥G3 AE. ≥G3 AE rates by line of tx were 62.5% (2L), 50% (3L), and 45% (≥4L). Conclusions: ICI/TKI combination therapy is effective and safe beyond the 1L setting. Prior tx history appears to impact efficacy but has less of an effect on safety/tolerability. These observations will need to be confirmed in prospective studies.[Table: see text]

Bevacizumab, etoposide, and cisplatin (BEEP) in brain metastases of breast cancer progressing from radiotherapy: Results of the first stage of a multicenter phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1079-1079 ◽  
Author(s):  
Yen-Shen Lu ◽  
Wei-Wu Chen ◽  
Ching-Hung Lin ◽  
Ling-Ming Tseng ◽  
Dah-Cherng Yeh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Promising Result ◽  
Objective Response ◽  
Whole Brain Radiotherapy ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Moderate Activity ◽  
Breast Cancer Patients ◽  
Brain Radiotherapy ◽  
Study Results

1079 Background: With a general prolongation of survival, brain metastasis (BM) has become a common complication of breast cancer. However, management of BM remains a severe challenge. We hypothesized that bevacizumab (BE) could significantly enhance drug delivery of etoposide (E) and cisplatin (P), two of the cytotoxic agents that have moderate activity in BM of breast cancer, to brain tumors and thereby improve the efficacy. Methods: Breast cancer patients (pts) with BM progression after whole brain radiotherapy (WBRT) were enrolled. Pts received BE 15 mg/kg day 1, and E 70 mg/m2/day, days 2-4, P 70 mg/m2/day, day 2, every 21 days for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. Using a Simon’s optimal two-stage design with 15% as a minimum interest in CNS-OR rate (by intent to treat analysis), 11 pts were needed at the first stage; and a total of 31 evaluable for the whole study. Results: Among 16 pts enrolled from Jan 2011 to Jan 2012, 12 pts were evaluable for treatment response at the time of abstract submission. Median age was 55 (range 34-66); 1 pt was ER+HER2-, 5 pts were HER2+, and 6 pts were ER-HER2-. The median treatment cycles were 4.5 (range 1-6). Nine of 12 pts (75%; 95%CI 42.8-94.5) achieved CNS-OR including 6 pts (50%) with ≥80% and 3 pts (25%) with 50-80% CNS volumetric reduction, respectively. Two pts had non-CNS disease progression while CNS tumors remained under control. The median CNS progression free survival was 6.6 months (95% CI 0.8-12.4). Grade 3 /4 toxicities included neutropenia, leukopenia, anemia, and platelet in 13 (25.5%), 6 (11.8%), 2 (3.9%), and 2 (3.9%) cycles, respectively. Seven pts (58.3%) had received dose reduction to E 60 mg/m2 and P 60 mg/m2. Early reporting of this study was approved by Data and Safety Monitoring Committeedue to an extremely promising result. Conclusions: BEEP regimen has a significant anti-tumor effect for BM of breast cancer which progresses after WBRT.

Association of matrix metalloproteinase 2 (MMP2) baseline plasma level to objective response (OR), progression free survival (PFS), and overall survival (OS) and changes under treatment in patients treated with bevacizumab (Bev) for recurrent high-grade glioma (HGG).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2024-2024 ◽  
Author(s):  
Emeline Tabouret ◽  
Francoise Boudouresque ◽  
Jaime Callego Perez-Larraya ◽  
Maryline Barrie ◽  
Giuseppe Lombardi ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Baseline Level ◽  
Randomized Clinical Trials ◽  
Objective Response ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Cytotoxic Agents ◽  
Matrix Metalloproteinase 2 ◽  
Tumor Control ◽  
Multiple Time

2024 Background: Predictive marker of Bev activity is an unmet medical need. We evaluated predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent HGG treated with Bev. Methods: A set of eleven prebiomakers of interest (VEGF, VEGF-R2, bFGF, SDF1, PlGF, uPA, PAI1, MMP2, MMP7, MMP9, and adrenomedulline) were analyzed in plasma, using ELISA, at baseline from Bev initiation in a prospective cohort of 26 patients (Cohort1). Correlations were validated in a separate retrospective Bev treated cohort (Cohort2; n = 50) and then tested in a cohort of patients treated with cytotoxic agents without Bev (Cohort3; n = 34). Dosages were correlated to OR, PFS, and OS. MMP2 and MMP9 were then analyzed at multiple time points up to progression. Results: In cohort1, high MMP2 baseline level was associated with an OR rate of 83.3% for high levels versus 15.4% for low MMP2 levels (p = 0.001). In multivariate analysis, MMP2 baseline level was correlated with PFS (hazard-ratio (HR), 3.92; 95% confidence-interval (CI):1.46-10.52; p = 0.007) and OS (HR, 4.62; 95%CI 1.58-13.53; p = 0.005), as MMP9 (p = 0.016 for PFS and p = 0.025 for OS). Similar results were found in cohort2 for MMP2, (MMP2: p<0.001 for OR; p = 0.009 for PFS; p = 0.009 for OS) but not for MMP9. In cohort3, no association was found between MMP2, MMP9 and outcome. Significant changes in MMP2 and MMP9 plasma levels were observed during treatment. MMP2 increased after Bev initiation (p = 0.002), and decreased at progression (p = 0.002) while MMP9 initially decreased (p = 0.007) then increased at progression (p = 0.031). Conclusions: In patients with recurrent HGG treated with bevacizumab, but not with cytotoxic agents, high MMP2 plasma levels are associated with prolonged tumor control and survival while changes over time may reflect tumor control. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role should be reassessed.

Multi-analyte liquid biopsies based treatment in advanced refractory cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15623-e15623
Author(s):  
Sewanti Limaye ◽  
Darshana Patil ◽  
Dadasaheb B Akolkar ◽  
Timothy Crook ◽  
Anantbhushan Ranade ◽  
...  
Keyword(s):  
Treatment Response ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Single Gene ◽  
Objective Response ◽  
Specific Treatment ◽  
Patient Specific ◽  
Solid Organ ◽  
Liquid Biopsies ◽  
Blood Draw

e15623 Background: Tumor tissue profiling following invasive biopsies is presently the standard approach for indication-based therapy management in solid organ cancers. However, challenges in biopsy are traditionally described due to proximity to vital organs, or patients’ co-morbidities or unwillingness for an invasive procedure. Liquid biopsies for evaluation of cancers are also largely restricted to single gene testing for selection of targeted therapy agents. We developed a comprehensive liquid biopsy based multi-analyte (molecular and functional) investigation of the cancer (eLBx: Encyclopedic Liquid Biopsy) for selection and management of individualised treatments in a cohort of advanced refractory cancers. Methods: We obtained 20 mL blood from 65 patients with solid organ cancers where the disease had progressed following failure of at least two lines of systemic therapies and where biopsy to obtain tumor tissue for molecular profiling of tumor was unviable. Cell free tumor DNA (ctDNA) was interrogated for mutations, while exosomal mRNA was profiled for gene expression. Viable circulating tumor associated cells (C-TACs) were tested in vitro for chemoresistance and used to determine expression of cell surface signalling receptors by immunocytochemistry (ICC). The findings were integrated to generate patient-specific treatment regimens. In patients who received treatment, response was determined radiologically. Results: Fifty-one patients received eLBx-guided personalized treatments with combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Forty-three patients were evaluable for treatment response per protocol among whom Partial Response (PR) was observed in 14 patients yielding an Objective Response Rate (ORR) of 32.6%. Additionally, 23 patients showed Stable Disease thus yielding an overall Disease Control rate of 86.1%. Median Progression Free Survival (PFS) was 108 days. There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: The ability to make informed treatment choices from a convenient blood draw implies a reduced dependence on invasive biopsies for disease management. We demonstrate successful management of advanced refractory solid tumor malignancies using an integrational non-invasive multi-analyte liquid biopsy approach. Clinical trial information: CTRI/2019/02/017548.

Results of a phase II study of capecitabine-based doublets in the treatment of metastatic triple-negative breast cancer (mTNBC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11538-e11538
Author(s):  
Ying Fan ◽  
Binghe Xu ◽  
Yuqian Liao ◽  
Fei Ma ◽  
Peng Yuan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Free Survival ◽  
Metastatic Setting ◽  
Secondary Endpoints

e11538 Background: It is extremely important to identify proper cytotoxic agents for TNBC which had limited choices except chemotherapy. Capecitabine are well established as a major chemotherapeutic agent in metastatic setting. The efficacy of capecitabine-based chemotherapy has not been prospectively studied in TNBC and data remains scant. This study was designed to investigate the efficacy of capecitabine-based doublets in the treatment of metastatic TNBC. Methods: Eligible metastatic TNBC women with measurable diseases were recruited to receive either TX regimen (docetaxel 75mg/m2 iv d1 plus capecitabine 1000mg/m2 bid, d1-14,q3w) or NX regimen (vinorelbine 25mg/m2 iv d1, 8 plus capecitabine 1000mg/m2 bid, d1-14, q3w) at the discretion of physicians for up to 6 cycles, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate and secondary endpoints included progression free survival (PFS), overall survival (OS). Results: 45 mTNBC patients, 27 in TX and 18 in NX were recruited, mostly (73.3%) as 1st line and the remaining as the 2nd line. The total objective response rate was 20.0% and clinical benefit rate was 62.2%. After a median follow-up of 28 months, PFS was 5.2 months (95%CI, 4.1-6.3mons) and OS was 18.2months (95%CI, 8.7-27.7mons). Almost half of the patients (22/45) progressed during treatment or within one month of the treatment discontinuation. PFS was significantly longer if patients got CR/PR (9.6 vs 4.3mons, P=0.015). When comparing two doublets, the response rate was numerically but not statistically lower in TX group than in NX group (14.8% vs 27.8%, P=0.449). Similarly, no difference was found in either PFS (4.9 vs 5.2 mons, P=0.483) or OS (21.5 vs 18.3 mons, P=0.964) between two regimens. Conclusions: Although the overall survival seems to be reasonable, efficacy of capecitabine-contained TX or NX regimen was relatively poor in terms of tumor remission and progression free survival in mTNBC patients, suggesting capecitabine may have limited potency in this subtype. These two combinations may be considered to be acceptable but may not be recommended as prior choice for mTNBC patients.

HALO 109-301: A randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 638-638 ◽  
Author(s):  
Margaret A. Tempero ◽  
Eric Van Cutsem ◽  
Darren Sigal ◽  
Do-Youn Oh ◽  
Nicola Fazio ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Objective Response ◽  
Progression Free Survival ◽  
Geographic Region ◽  
Ductal Adenocarcinoma ◽  
Sample Treatment ◽  
Bleeding Events ◽  
Phase 3 ◽  
Double Blind ◽  
Secondary Endpoints

638 Background: HA is a major component of the tumor microenvironment (TME) in PDA. PEGPH20 degrades tumor HA, remodeling the TME. In PDA models, PEGPH20 has shown antitumor activity and increased TME delivery of anticancer agents to improve efficacy. A randomized phase 2 study showed promising results for PEGPH20+AG (PAG) in mPDA and identified HA accumulation as a biomarker. We present results from a phase 3 study (NCT02715804) of PAG for pts with HA-high mPDA. Methods: Pts ≥18 years with untreated HA-high mPDA were randomized (stratified by geographic region) 2:1 to PAG or placebo+AG (AG). HA status was prospectively determined with VENTANA HA RxDx Assay, with HA-high defined as ≥50% staining of a tumor sample. Treatment was administered IV in 4-wk cycles (3 wks on, 1 wk off) until progression or intolerable adverse events (AEs): PEGPH20 3.0 µg/kg twice wkly for Cycle 1 and once wkly (QW) thereafter, A 125 mg/m2 QW and G 1000 mg/m2 QW. Prophylactic enoxaparin 1 mg/kg was given daily for thromboembolism (TE) risk. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. Response was independently assessed per RECIST v1.1. The estimated sample size was ~500 pts to detect a hazard ratio (HR) for OS of 0.67 (93% power, 2-sided α = 0.05) after 330 deaths. Results: As of 20 May 2019, 494 pts were randomized with 492 (327 for PAG and 165 for AG) included in ITT analyses (2 pts excluded due to site violations). Baseline characteristics were balanced for PAG vs AG. After 330 deaths, median OS for PAG vs AG was 11.2 vs 11.5 mo (HR 1.00, 95% CI 0.80–1.27; P = 0.97); median PFS was 7.1 vs 7.1 mo (HR 0.97, 95% CI 0.75–1.26); confirmed ORR was 34% vs 27%. Grade (G) 3+ AEs (PAG vs AG) included neutropenia (44% vs 47%), thrombocytopenia (21% vs 16%) and fatigue (16% vs 10%); G3+ rates were 6% vs 7% for TE events, 5% vs 2% for bleeding events and 13% vs 5% for musculoskeletal events. Conclusions: PAG did not improve clinical outcomes vs AG. The PAG safety profile was consistent with that of previous studies. Clinical trial information: NCT02715804.

scholarly journals Clinical efficacy of combination therapies with androgen receptor antagonists for treatment of multiple refractory cancers.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 115-115
Author(s):  
Dadasaheb B Akolkar ◽  
Darshana Patil ◽  
Vineet Datta ◽  
Ajay Srinivasan ◽  
Rajan Datar
Keyword(s):  
Androgen Receptor ◽  
Treatment Response ◽  
Clinical Benefit ◽  
Objective Response ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Disease Status ◽  
Solid Organ ◽  
Combination Treatments

115 Background: Androgen Receptor (AR) antagonists have been the mainstay of prostate cancer treatments. However, there is increasing interest in the use of anti-AR agents in treatment of other cancers such as Triple Negative Breast Cancer and Lung Cancer. AR antagonists are usually administered as single agents and rarely in combination with other cytotoxic or targeted agents. We hypothesized that administration of AR antagonists indicated by Encyclopedic Tumor Analysis (ETA) in synergistic combination with cytotoxic, targeted or other endocrine agents may afford clinical benefit for refractory cancers. Methods: We evaluated treatment response in a basket of 18 patients with various advanced refractory solid organ malignancies, who received personalized treatments based on ETA investigations. As part of ETA, freshly biopsied tumor tissue and blood samples were evaluated for various markers such as gene mutations (DNA), gene expression (RNA) and receptor proteins (immunohistochemistry). Finally, viable tumor cells from the freshly biopsied tissue were used in in vitro chemosensitivity analysis with a panel of cytotoxic and targeted therapy agents. Radiological disease status was evaluated retrospectively and treatment response as well as Progression Free Survival (PFS) was determined. Results: Among the 18 patients, there were 8 males (44%) and 10 females (56%) with median age of 58 years (range 28 – 79). Patients had received a median of 3 prior lines of treatment (range 1 – 14). All 18 patients received ETA guided combination treatments which included an AR blockade. 9 patients showed Partial Response ( PR) with an Objective Response Rate (ORR) of 50%. 5 patients (28%) showed stable disease for ≥3 months (Clinical Benefit Rate = 77.8%), while 4 patients (22%) showed disease progression. In 2 patients (11%) disease progressed at ~60 days and in the remaining 2 patients (11%) progression was seen at > 120 days. Treatments were well tolerated without severe adverse events. Conclusions: Androgen addicted, refractory solid organ tumors respond to combinations of cytotoxic, targeted and endocrine agents along with AR antagonists guided by ETA.

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