GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial.

PURPOSE: The GODDESS© tool was developed to assess Desmoid Tumor/Aggressive Fibromatosis (DT/AF) symptom severity and impact on patients' lives. This study evaluated GODDESS©'s cross-sectional and longitudinal measurement properties. METHODS: The Phase 3, randomized placebo-controlled, DeFi study (NCT03785964) of nirogacestat in DT/AF was used to assess GODDESS©'s reliability, construct validity, responsiveness, and estimate of meaningful change thresholds (MCTs). Other patient-reported outcome (PRO) measures included Patient Global Impression of Severity (PGIS) in DT/AF symptoms, EORTC QLQ-C30, Brief Pain Inventory Short Form, and PROMIS Physical Function short-form 10a v2.0 plus 3 items. RESULTS: DeFi participants (N = 142) had a median age of 34 years (range: 18-76) and were mostly female (64.8%), with extra-abdominal (76.8%) or intra-abdominal tumors (23.2%). The GODDESS© symptom/impact scales showed internal consistency at baseline, cycles 4 and 7 (Cronbach's α > 0.70) and test-retest reliability (intra-class correlation coefficient > 0.85). GODDESS© scales correlated moderately to highly with PRO measures capturing similar content and differentiated among PGIS and Eastern Cooperative Oncology Group groups. GODDESS© scales detected improvement over time. For the total symptom score, a 1.30-point decrease was estimated as the within-person MCT and a 1.00-point decrease as the between-group MCT. For the physical functioning impact score, estimated within- and between-group MCTs were 0.60-point and 0.50-point decreases, respectively. Few participants exhibited symptom worsening. CONCLUSION: GODDESS© was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses. TRIAL REGISTRATION NUMBER AND REGISTRATION DATE: NCT03785964; December 24, 2018.

Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors.

PURPOSE: This phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: This trial used a standard 3 + 3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy. RESULTS: The trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common ≥grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8-not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months-NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic response and durable clinical benefit. CONCLUSIONS: The combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.

A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma.

PURPOSE: Because the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma. PATIENTS AND METHODS: In this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib. RESULTS: Nine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch. CONCLUSIONS: The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling.

Phase II Trial of Imatinib Plus Binimetinib in Patients With Treatment-Naive Advanced Gastrointestinal Stromal Tumor.

PURPOSE: Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST. METHODS: In this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity. RESULTS: Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%). CONCLUSION: The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.