ICEPAC: A phase II multicenter study of avelumab combined with stereotactic ablative body radiotherapy (SABR) in metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 86-86
Author(s):  
Arun Azad ◽  
Lavinia Anne Spain ◽  
Angelyn Anton ◽  
Chun Loo Gan ◽  
Linda Garrett ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Disease Control ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Checkpoint Inhibitors ◽  
Disease Assessment ◽  
Castration Resistant Prostate Cancer ◽  
Protocol Amendment ◽  
Stereotactic Ablative Body Radiotherapy ◽  
Taxane Chemotherapy

86 Background: Studies investigating immune checkpoint inhibitors (ICI) in mCRPC have produced modest results. Radiation therapy may be synergistic with ICIs. We hypothesised that SABR would enhance anti-tumour activity of PD-L1 inhibitor avelumab in patients (pts) with progressive mCRPC. Methods: This phase II, single arm, multicentre study enrolled mCRPC pts following progression on ≥1 novel androgen receptor-directed therapy. Up to two lines of prior taxane chemotherapy were permitted. Pts received avelumab 10mg/kg IV q2weeks for a total of 24 weeks (12 cycles). A single fraction of 20Gy SABR was administered to 1-2 disease sites within five days prior to first and second doses of avelumab. Primary endpoint was disease control rate (DCR); secondary endpoints were PSA response (PSA50), overall response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS) and safety. Radiographic disease assessment (CT and bone scintigraphy) was performed after cycles 6 and 12 of avelumab treatment. Following enrolment of 14 pts, a protocol amendment allowed avelumab beyond 12 cycles in pts with disease control at 24 weeks. Results: Thirty-one pts were enrolled, with 30 evaluable for the primary endpoint. Median follow-up was 18 months (mo). Pt characteristics: median age 71 years (IQR 64-75), bone-only disease 42%, visceral disease 16%, prior taxane chemotherapy 84%, treatment with both abiraterone and enzalutamide 13%. Seventy metastatic sites received SABR, most frequently to bone (90%) and soft tissue (29%) disease. Avelumab was given as second-line, third-line and fourth- or greater line systemic therapy in 29%, 42% and 29% of pts, respectively. Median cycles of avelumab administered was 9 (IQR 5-13). DCR (95% CI) was 50% (31-69) and 60% (32-84) in all-comers and soft tissue disease subgroup, respectively. Following protocol amendment, 7/17 pts (41%) received avelumab beyond 12 cycles. Incidence of grade 3-4 treatment-related AEs was 16% (no grade 5 events), with three pts requiring oral/IV corticosteroid therapy. Conclusions: Avelumab with SABR demonstrated durable disease control in treatment-refractory mCRPC with an acceptable toxicity profile. This combination warrants further investigation. Clinical trial information: ACTRN12618000954224. [Table: see text]

TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5005-5005 ◽  
Author(s):  
Joaquin Mateo ◽  
Nuria Porta ◽  
Ursula Brigid McGovern ◽  
Tony Elliott ◽  
Robert J Jones ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Response Rates ◽  
Damage Repair ◽  
Altered Gene ◽  
Prostate Cancers ◽  
Taxane Chemotherapy

5005 Background: We previously reported the antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC (TOPARP-A; Mateo et al NEJM 2015). We now report TOPARP-B, a phase II trial for patients with mCRPC preselected for putatively pathogenic DDR alterations. Methods: Patients with mCRPC progressing after ≥ 1 taxane chemotherapy underwent targeted sequencing of tumor biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DDR gene were detected. Patients were randomized 1:1 under a “pick-the-winner” design to 400mg or 300mg of olaparib BID, aiming to exclude ≤30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to < 5), confirmed after 4-weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included progression-free survival (PFS), tolerability. Results: Overall, 98 patients (median age 67.6y) were randomized, with 92 patients treated and evaluable for the primary endpoint (70 RECIST-evaluable; 89 PSA50%-evaluable; 55 CTC-evaluable). All had progressed on ADT; 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel. The overall RR was 54% (95%CI 39-69%, meeting threshold for primary endpoint) in the 400mg cohort and 37% (95%CI 23-53%) in the 300mg cohort. With a median follow-up of 17.6 months (mo), the overall median PFS (mPFS) was 5.4 mo. Subgroup analyses per altered gene identified indicated response rates for: BRCA1/2 of 80% (24/30; mPFS 8.1mo); PALB2 57% (4/7; mPFS 5.3mo); ATM 37% (7/19; mPFS 6.1mo); CDK12 25% (5/20; mPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mPFS 2.8mo). The highest PSA50% response rates were observed in the BRCA1/2 (22/30; 73%) and PALB2 (4/6; 67%) subgroups. Conclusions: Olaparib has antitumor activity against heavily pre-treated mCRPC with DDR gene defects, with BRCA1/2 aberrant tumors being most sensitive but with confirmed responses in patients with other DDR alterations. Clinical trial information: NCT01682772.

A phase II trial cohort of nivolumab plus ipilimumab in patients (Pts) with recurrent/metastatic adenoid cystic carcinoma (R/M ACC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6084-6084 ◽  
Author(s):  
Vatche Tchekmedyian ◽  
Eric Jeffrey Sherman ◽  
Lara Dunn ◽  
James Vincent Fetten ◽  
Loren S. Michel ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Trial ◽  
Malignant Neoplasm ◽  
Checkpoint Blockade ◽  
Disease Assessment ◽  
Separate Analysis ◽  
Type I ◽  
Overall Response ◽  
The Impact

6084 Background: R/M ACC is a malignant neoplasm most commonly of salivary gland origin with no standard treatment. The impact of combined PD-1/CTLA-4 checkpoint blockade in R/M ACC is unknown. Methods: In a two-stage minimax phase II trial, pts with progressive R/M ACC (non-salivary primaries allowed) were enrolled and treated with nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (1 cycle = 6 weeks). Imaging, using RECIST v1.1 response assessment, was scheduled to be performed approximately every 12 weeks. The primary endpoint was overall response rate (ORR = complete response [CR]+partial response [PR]) per RECIST v1.1. To detect a difference between an unacceptable ORR of 5% and a desirable ORR of 20% (one-sided type I error of 10%, power of 90%), at least 1 in the first 18 pts required an observed response. At least 4 responses of 32 total pts were needed to meet the primary endpoint. Treatment beyond progression of disease (PD) was allowed at the discretion of the investigator. A second cohort of pts with non-ACC salivary cancer is still accruing for separate analysis. Results: From 6/12/2017-6/20/2018, 32 pts were enrolled and evaluable for the primary endpoint. There was 1 confirmed PR in the first 18 pts, therefore enrollment of the second stage continued. ORR was 6% (2/32). One additional pt had an unconfirmed PR (-31% regression before CNS PD). For best overall response, there were 2 PRs, 15 SD, and 11 PD. Four pts never reached a first disease assessment: 3 due to death from clinical PD and 1 was removed for toxicity. Six pts discontinued the trial for toxicities (Grade 4 (G4) neutropenia/sepsis and G3 adrenal insufficiency (1), G2 hypophysitis (2), G3 arthritis > 7 days (1), G3 colitis (1), and G3 hepatitis/G4 creatinine kinase (CK) elevation (1)). The 2 confirmed PRs consisted of -73.1% and -58.4% regressions, with a duration of therapy of 18.4 and 7.8 months, respectively (treatment ongoing for both). Conclusions: The study did not meet its primary endpoint, though the responses observed were dramatic. Paired biopsy and peripheral blood samples will be analyzed to elucidate insights into mechanisms of response and resistance to dual checkpoint blockade. Clinical trial information: NCT03172624.

A randomized phase II study of durvalumab and tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma (MEDISARC, AIO-STS 0415).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS11075-TPS11075
Author(s):  
Viktor Grünwald ◽  
Sebastian Bauer ◽  
Barbara Hermes ◽  
Philipp Ivanyi ◽  
Lars H Lindner ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Soft Tissue ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Soft Tissue Sarcomas ◽  
Predictive Biomarkers ◽  
Ecog Performance Status ◽  
Curative Intent

TPS11075 Background: Soft tissue sarcomas (STS) are rare tumors and exhibit substantial histological diversity. Efficacious targeted 1st line treatment for advanced or metastatic STS is not available, and the standard therapy has been anthracycline-based for decades. This strategy shows poor efficacy, as demonstrated by a median Overall Survival (OS) of 12-20 months. Several STS subtypes, however, have been shown to express PD-L1, and immune checkpoint inhibitors (ICI) have demonstrated principle anti-tumor activity in pretreated STS. Our ongoing clinical trial tests the activity and safety of ICI combination therapy in the first-line setting. We hypothesize that the dual checkpoint blockade with Durvalumab (PD-L1) and Tremelimumab (CTLA-4) improves overall survival in STS when compared to the standard of care doxorubicin. Methods: MEDISARC is a multi-center phase II trial that is enrolling adult treatment-naïve patients with histologically confirmed STS of intermediate or high grade (FNCLCC grade 2 or 3) not amenable to surgery with curative intent and ECOG performance status 0-2. Chemosensitive histologic STS are eligible. 100 patients will be randomized 1:1, stratified by ECOG status (0 vs. 1/2). Patients in the experimental arm are treated with fixed doses of durvalumab (1.5 g Q4W) and tremelimumab (75 mg Q4W for 3 cycles, then Q12W) until Progressive Disease (PD) or for a maximum of 12 months. Doxorubicin treatment in the standard arm is at 75 mg/m2 Q3W and limited to 6 cycles. OS is the primary endpoint. Secondary endpoints include 2-year OS rate, PFS, ORR according to conventional and modified RECIST 1.1, safety and tolerability and health-related quality of life (EORTC QLQ-C30). OS analysis may be performed when the required number of events (E=70) has been observed. All randomized and treated subjects will be included in the efficacy and safety analysis. The accompanying translational research aims to identify prognostic and predictive biomarkers in blood and tumor tissue. Enrollment of patients started in April 2018 and is ongoing. As of February 2019, 32 patients have been enrolled. The study is sponsored by AIO-Studien-gGmbH, Berlin, Germany. Clinical trial information: 2016-004750-15.

A phase II study of anti-PD1 monoclonal antibody (Nivolumab) administered in combination with anti-LAG3 monoclonal antibody (Relatlimab) in patients with metastatic melanoma naive to prior immunotherapy in the metastatic setting.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS10085-TPS10085
Author(s):  
Anjali Rohatgi ◽  
Ryan Campbell Massa ◽  
William E. Gooding ◽  
Tullia C. Bruno ◽  
Dario Vignali ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Disease Assessment ◽  
Survival Duration ◽  
Metastatic Setting

TPS10085 Background: Novel checkpoint inhibitors are a promising treatment for advanced melanoma, as only a fraction of patients have durable responses to current FDA-approved immunotherapy. Lymphocyte activation gene 3 (LAG3) is an inhibitory checkpoint receptor on CD4+ and CD8+ T cells, where engagement results in suppression of T cell activation and proliferation. LAG3 and PD1 are co-expressed on T cells during T cell receptor signaling and are down-regulated after antigen clearance. Persistent stimulation leads to prolonged LAG3 and PD1 expression and to T cell exhaustion, a possible mechanism of resistance to immunotherapy. Both LAG3 and PD1 are expressed on tumor-infiltrating T cells in melanoma. Murine tumors treated with both anti-LAG3 and anti-PD1 have demonstrated increased tumor regression than tumors in mice treated with either single agent. Further, a phase I trial has demonstrated safety of combined anti-LAG3 monoclonal antibody, relatlimab and anti-PD1 monoclonal antibody, nivolumab. Methods: This phase II, single-center clinical trial is designed to enroll treatment naive patients with unresectable or metastatic melanoma to ultimately receive combined relatlimab and nivolumab after a lead-in arm where patients are randomized to receive relatlimab, nivolumab, or the combination for the first 4 week cycle. For the lead-in phase, patients will have baseline and post-treatment blood and tumor sampling. Disease assessment by imaging will occur after the lead-in phase at 4 weeks. After completion of the lead-in phase, all patients proceed to combination therapy with disease assessment at 12-week intervals. The primary endpoint for the lead-in phase is to evaluate changes in immune cell populations in peripheral blood and tumor with the single agents and combination treatment. The primary endpoint for the combination phase is best overall anti-tumor response. Secondary clinical endpoints include progression-free survival, overall survival, duration of response and toxicity. Exploratory endpoints are to determine the mechanistic effects of anti-LAG3 and anti-PD1 on the blood and tumor microenvironment, cytokine signatures, and correlation of these with clinical response. The study is currently accruing with enrollment of 9 out of 42 patients. Clinical trial information: NCT03743766.

scholarly journals Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study

2014 ◽  
Vol 32 (30) ◽  
pp. 3391-3399 ◽  
Author(s):  
Matthew R. Smith ◽  
Christopher J. Sweeney ◽  
Paul G. Corn ◽  
Dana E. Rathkopf ◽  
David C. Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Soft Tissue ◽  
Tumor Cells ◽  
Phase Ii ◽  
Bone Scan ◽  
Castration Resistant Prostate Cancer ◽  
Bone Biomarkers ◽  
Castration Resistant ◽  
Analgesic Use

Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

scholarly journals A phase II trial of cabozantinib in hormone receptor-positive breast cancer with bone metastases.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1062-1062
Author(s):  
Jing Xu ◽  
Michaela Jane Higgins ◽  
Sara M. Tolaney ◽  
Steven E. Come ◽  
Matthew Raymond Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Disease Control ◽  
Bone Metastases ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Hormone Receptor ◽  
Bone Scan ◽  
Response Rate ◽  
Hormone Receptor Positive ◽  
Initial Starting

1062 Background: We assessed the antitumor activity of cabozantinib, a potent multi-receptor oral tyrosine kinase inhibitor with activity against MET, RET, VEGFR2, and AXL, in patients with hormone-receptor positive (HR+) breast cancer with bone metastases. Methods: In this single-arm multicenter phase II study, patients with HR+, HER2- metastatic breast cancer and ≥ 1 prior line of therapy received an initial starting dose of 100 mg cabozantinib, later reduced to 60 mg per day. The primary endpoint was bone scan response rate determined by independent central review and defined as percent change of bone scan area from baseline. The target bone scan response rate was 30% compared to a null response rate of 10%. Secondary endpoints included objective response rate (ORR) by RECIST v1.1, progression free (PFS) and overall survival (OS). Bone scan and CT were obtained every 12 weeks. Results: Among 52 enrolled patients, median age was 55, and 54% and 42% had > 2 lines prior endocrine and chemotherapy, respectively and 18 (35%) had bone-only disease. 20 (38%) experienced a partial bone scan response and 6 (12%) had stable disease (SD). 16 (31%) patients discontinued study prior to week 12 assessment for early clinical progression or toxicity, and three (6%) had missing follow-up scans. Best extra-osseous overall response revealed SD in 26 (50%), but no objective responses. In 25 patients with bone scan disease control at 12 weeks, only 3 (12%) developed extra-osseous progression. Median PFS was 4.3 months (90% CI 2.8 - 5.5) and OS was 19.6 months (90% CI 18.0 – 26.8). In a landmark analysis, patients with bone scan disease control at 12 weeks had longer OS (median 24.2 months, 90% CI 16.4 – 31.7) than those without (median OS 13.3 months, 90% CI 9.5 – 18.2), with a hazard ratio of 0.37 (90% CI 0.21 – 0.65). Most common grade 3 or 4 toxicities were hypertension (10%), anorexia (6%), diarrhea (6%), fatigue (4%) and hypophosphatemia (4%). Dose reduction or delay occurred in 42 (81%) patients. Conclusions: This study met its primary endpoint with bone scans improved in 38% of patients with metastatic HR+ breast cancer and remained stable in an additional 12% with cabozantinib treatment. Bone scan response correlated with improved OS. This is the first reported study in breast cancer to use bone scan response as a primary endpoint. Further studies with cabozantinib in HR+ breast cancer and additional validation of bone scan response as a surrogate for clinical benefit in breast cancer are warranted. Clinical trial information: NCT01441947 .

scholarly journals A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone

2020 ◽  
Vol 8 (2) ◽  
pp. e000642 ◽  
Author(s):  
Julie N Graff ◽  
Tomasz M Beer ◽  
Joshi J Alumkal ◽  
Rachel E Slottke ◽  
William L Redmond ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Specific Antigen ◽  
Subsequent Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Entire Cohort ◽  
Castration Resistant

BackgroundCheckpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response.MethodsWe evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens.ResultsFive (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression.ConclusionsPembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects.Trial registration numberclinicaltrials.gov (NCT02312557).

A phase II open-label trial of GTx-758 in men with castration-resistant prostate cancer: Final analysis of the primary endpoint.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 185-185
Author(s):  
Evan Y. Yu ◽  
Michael L. Hancock ◽  
Tamas Babicz ◽  
Ronald F. Tutrone ◽  
Christopher Ng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Androgen Receptor ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Open Label Trial ◽  
Lhrh Therapy

185 Background: Recently approved agents that target the androgen receptor pathway emphasize the importance of the persistent activity of the androgen receptor pathway in castration-resistant prostate cancer (CRPC). This raises the possibility that agents with distinct mechanisms of action may add value. GTx-758 is a selective ERα agonist that can increase SHBG and therefore reduce biologically active testosterone (T) levels. Reported here are the results, including the final primary endpoint analysis, from the 250 mg daily GTx-758 cohort of a phase II clinical trial in men on LHRH agonists that developed CRPC. Methods: This phase II open label trial (G200712, NCT01615120) treated men with high risk nmCRPC or mCRPC with T levels < 50 ng/dL who continued to receive their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. The primary endpoint was the proportion of men with a PSA decline ≥ 50% by day 90, while secondary endpoints included serum total and free T, sex hormone binding globulin (SHBG), bone turnover markers and hot flashes. Results: The 250 mg cohort (n = 39) has completed the time period for assessment of the primary endpoint. Ten of the 39 (26%) subjects exhibited a ≥ 50% decrease in PSA by Day 90, with 11/39 (28%) by Day 120, while 18/39 (46%) had PSA declines of ≥ 30%. Median SHBG levels increased 301% of baseline, confirming the principal mechanism of drug action. While on study, median free T decreases of 44% were observed across all subjects and 20/26 (77%) of the subjects with baseline serum free T levels > 0.7 pg/ml fell below this level. Therefore, 250 mg GTx-758 decreased free testosterone levels in an additive fashion to their existing LHRH therapy. The bone turnover biomarker, C-telopeptide, decreased in 79% of the subjects. 250 mg of GTx-758 has been generally well tolerated with two reported possibly drug related SAEs (VTE and MI). Conclusions: In this phase II trial, 250 mg daily GTx-758 has activity, likely mediated by lowering free T levels in patients with CRPC on LHRH therapy, and may provide amelioration of estrogen deficiency side effects associated with ADT. Clinical trial information: NCT01615120.

A phase II trial of regorafenib (REGO) in patients (pts) with advanced Ewing sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial results.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11005-11005 ◽  
Author(s):  
Steven Attia ◽  
Vanessa Bolejack ◽  
Kristen N. Ganjoo ◽  
Suzanne George ◽  
Mark Agulnik ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Common Grade ◽  
Duration Of Response ◽  
The Difference ◽  
Line Of Therapy

11005 Background: Pazopanib is approved for soft tissue sarcoma pts after failure of other therapy, but there are few subtype-specific data regarding kinase inhibitor activity. We report on a single arm, phase II trial of REGO in advanced EWS. Methods: EWS pts (age > 18, ECOG 0-2, good organ function) who had at least 1 line of therapy and had PD within 6 mo were eligible. Prior oral kinase inhibitors were not allowed. Initial REGO dose was 160 mg PO QD x21 q28d. Dose reductions were employed for toxicity and AEs. The primary endpoint was PFS at 8 weeks (PFS8w) employing RECIST 1.1. Sample size of 30 allowed determination of the difference between PFS8w of 50% vs 25% with alpha = 0.05 and power of 91%. Results: 30 pts (median age 32, range 19-65; M/F = 20/10; ECOG 0/1/2 = 16/13/1; bone, 12; soft tissue, 18; median prior treatments 5, range 1-10) enrolled at 14 US sites (09/2014-03/2016). Most common grade (G3) toxicities were hypophosphatemia (6), hypertension (2), high ALT (2) and 1 each: fatigue, abd pain, diarrhea, hypokalemia, oral mucositis, neutropenia and rash; no G4 toxicities were noted. 13 pts required ≥1 dose reduction, most commonly hypophosphatemia (n = 7); 2 stopped REGO for toxicity. There was 1 death in the 30 day post study period, not REGO related. Median dose at study end: 140 mg (3.5 tabs, range 80-160 mg) 3 wks on/1wk off. 18/30 pts were without PD at 8 wks. Median PFS: 3.6 mo (95%CI 2.8-3.8 mo). PFS8w by KM was 73% (95%CI 57-89%). Best responses: PR/SD/PD/not evaluable of 3/18/7/2, for RECIST RR 10%. Two pts with PR had EWSR1 translocation by FISH; a third had CIC-DUX4. Median duration of response: 5.5 mo (95%CI 2.9-8.0). Median OS is not reached. Conclusions: The substudy met its primary endpoint. REGO toxicity was similar to that seen previously. Enrollment continues in LPS and OGS cohorts, and is being expanded to further study variant EWS without EWSR1-FLI1 fusion. Study of the existing tissue may elucidate which EWS patients may benefit from REGO. Clinical trial information: NCT02048371.

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