Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer

Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. Experimental Design: In ARMOR1, 49 patients received increasing doses (650–2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700–3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition

Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin

Abstract Background The NAPOLI-1 study (NCT01494506) reported that liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) improved overall survival vs 5-FU/LV with manageable toxicity in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Yet, clinicians need treatment strategies that also maintain the patient's health-related quality of life (HRQOL). Here, we report the HRQOL data. Methods Patients completed the European Organisation for Research and Treatment of Cancer QOL core questionnaire C30 (EORTC QLQ-C30) at baseline, every 6 weeks, and at 30 days after discontinuation of study treatment. Patient-reported outcomes (PROs) were scored according to EORTC guidelines. nal-IRI+5-FU/LV HRQOL was compared with 5-FU/LV. The PRO population comprised intent-to-treat patients who completed baseline and at least one subsequent assessment on the EORTC QLQ-C30. Data were also analysed for missingness. Results Of 236 patients in the intent-to-treat population, 128 (54.2%) comprised the PRO population (71 in the nal-IRI+5-FU/LV arm; 57 the in 5-FU/LV arm). Of the remaining 108 patients (45.8%) not included in the PRO population, most progressed rapidly, making participation difficult. Median change from baseline was ≤10 points at weeks 6 and 12 in global health status or functional and symptom scale scores, except for fatigue, which deteriorated by 11.1 points with nal-IRI+5-FU/LV but did not change vs 5-FU/LV. The proportion of patients whose HRQOL improved or deteriorated was not significantly different between the arms. Conclusion In the NAPOLI-1 study, HRQOL was maintained with nal-IRI+5-FU/LV in patients with metastatic pancreatic adenocarcinoma previously treated with a gemcitabine-based regimen, while survival was significantly extended

Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST)

11022 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Updated results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Safety from the overall population (30-600 mg doses) and efficacy in the response evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 (56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with median duration of response (mDOR) of 10.2 months (95% CI: 7.2-NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3-NE). Most AE were grade 1-2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3-4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2 nd and 3 rd line therapies and shows unprecedented activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532

AVAPRITINIB IS HIGHLY ACTIVE AND WELL-TOLERATED IN PATIENTS (PTS) WITH ADVANCED GIST DRIVEN BY DIVERSE VARIETY OF ONCOGENIC MUTATIONS IN KIT AND PDGFRA

status: publishe