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Normalized Kynurenine Concentrate Over Time

Normalized Tryptophan Concentrate Over Time

Purpose:Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes.Patients and Methods:This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1.Results:Thirty patients were enrolled [60% male; median age 54 years (range, 24–78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%–17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9–26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway–related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline.Conclusions:Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.

Representativeness of study participants.

Supplementary Methods and Legends PDF file - 72K, Includes detailed methods for 5' RACE assay and DCE-MRI scans, as well as figure legends for the six supplementary figures

Supplementary Figure 1 depicts copy number alterations in the described cohort

Supplementary Table 1 shows point mutations found in DSRCT samples

Supplementary Figure 3 provides a breakdown of the structural variant types found via whole genome sequencing in DSRCT samples

Supplementary Figure 2 depicts whole genome sequencing findings

Supplementary Figures PDF file - 114K, Includes sequence information on KSP and VEGF siRNAs, murine Hep3B tumor model data with ALN-VSP, ALN-VSP Phase I study design, KSP and VEGF mRNA levels in tumor cell lines and normal liver, and comparison of ALN-VSP PK data in cancer patients and non-human primates

Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1–WT1 t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of model systems. Next-generation sequencing (NGS) data from 68 matched tumor-normal samples, whole-genome sequencing data from 10 samples, transcriptomic and affymetrix array data, and a bank of DSRCT patient-derived xenograft (PDX) are presented. EWSR1–WT1 fusions were noted to be simple, balanced events. Recurrent mutations were uncommon, but were noted in TERT (3%), ARID1A (6%), HRAS (5%), and TP53 (3%), and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q was identified in 18%, 22%, and 34% of samples, respectively. Comparison of tumor-normal matched versus unmatched analysis suggests overcalling of somatic mutations in prior publications of DSRCT NGS data. Alterations in fibroblast growth factor receptor 4 (FGFR4) were identified in 5 of 68 (7%) of tumor samples, whereas differential overexpression of FGFR4 was confirmed orthogonally using 2 platforms. PDX models harbored the pathognomic EWSR1–WT1 fusion and were highly representative of corresponding tumors. Our analyses confirm DSRCT as a genomically quiet cancer defined by the balanced translocation, t(11;22)(p13:q12), characterized by a paucity of secondary mutations but a significant number of copy number alterations. Against this genomically quiet background, recurrent activating alterations of FGFR4 stood out, and suggest that this receptor tyrosine kinase, also noted to be highly expressed in DSRCT, should be further investigated. Future studies of DSRCT biology and preclinical therapeutic strategies should benefit from the PDX models characterized in this study.Implications:These data describe the general quiescence of the desmoplastic small round cell tumor (DSRCT) genome, present the first available bank of DSRCT model systems, and nominate FGFR4 as a key receptor tyrosine kinase in DSRCT, based on high expression, recurrent amplification, and recurrent activating mutations.

Supplementary Figure 4 shows data related to FGFR4 inhibition in DSRCT and control models

Supplementary Tables PDF file - 67K, Includes data showing effect of ALN-VSP on spleen in non-human primates, tumor response data from the Phase I trial, and safety data (including adverse events and dose-limiting toxicities) from the Phase I trial

Supplementary Table 2 shows the raw data further described in Figure 3

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.

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.

Patients with brain metastases are increasing in number; however, these patients are often excluded in phase I/II trials due to perceived poor prognosis, risk of hemorrhage, inefficient drug delivery, and confounding toxicities. Tsimberidou and colleagues demonstrate that selected patients can be appropriately enrolled in phase I trials and have outcomes representative of the general cancer population. Clin Cancer Res; 17(12); 3855–7. ©2011 AACR.

Supplementary Figure 1. Of 16 patients (7 with and 9 without germination) with available data, 11 (69%) had a decrease in tumor density (-4% to -476%). The most robust decreases in density were observed in patients with germination. Supplementary Figure 2. Tumor antigen specific T-cell responses after C. novyi injection. Supplementary Figure 3. Infiltration in the injected and non-injected tumors.

Legends to Supplemental Figures

Supplementary Table from Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma

Supplementary Materials and Methods Supplementary Table 1

Related Article from Inclusion of Patients with Brain Metastases in Phase I Trials: An Unmet Need

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

Purpose:Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation.Patients and Methods:This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.Results:Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses.Conclusions:Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.

CONSORT Diagram.

Supplementary Legend

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

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.

Purpose: Phase I studies rely on investigators to accurately attribute adverse events as related or unrelated to study drug. This information is ultimately used to help establish a safe dose. Attribution in the phase I setting has not been widely studied and assessing the accuracy of attribution is complicated by the lack of a gold standard. We examined dose–toxicity relationships as a function of attribution and toxicity category to evaluate for evidence of toxicity misattribution.Experimental Design: Individual patient records from 38 phase I studies activated between 2000 and 2010 were used. Dose was defined as a percentage of maximum dose administered on each study. Relationships between dose and patient-level toxicity were explored graphically and with logistic regression. All P values were two-sided.Results: 11,909 toxicities from 1,156 patients were analyzed. Unrelated toxicity was not associated with dose (P = 0.0920 for grade ≥3, P = 0.4194 for grade ≥1), whereas related toxicity increased with dose (P < 0.0001, both grade ≥3 and ≥1). Similar results were observed across toxicity categories. In the five-tier system, toxicities attributed as “possibly,” “probably,” or “definitely” related were associated with dose (all P < 0.0001), whereas toxicities attributed as “unlikely” or “unrelated” were not (all P > 0.1).Conclusions: Reassuringly, we did not observe an association between unrelated toxicity rate and dose, an association that could only have been explained by physician misattribution. Our findings also confirmed our expectation that related toxicity rate increases with dose. Our analysis supports simplifying attribution to a two-tier system by collapsing “possibly,” “probably,” and “definitely” related. Clin Cancer Res; 22(3); 553–9. ©2015 AACR.See related commentary by Sharma and Ratain, p. 527

Dose-toxicity curves by agent class (cytotoxic or molecular) and attribution (2-tier system). Black points represent the proportion of patients in a dose group experiencing grade {greater than or equal to}1 toxicity with the specified category and attribution. Red points represent the proportion of patients experiencing grade {greater than or equal to}3 toxicity within the specified category and attribution. Lines represent a fitted logistic regression curve with % of maximum administered dose (MAD) as a continuous covariate and p-values are from the same model.

Purpose:Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors.Experimental Design:We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD.Results:We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline.Conclusions:In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management.

Supplementary Figure Legends

Demonstrates hypothetically the effect that systematic misattribution of disease-related toxicities as drug-related could have on the observed rate of drug-related toxicity as well as its relationship with dose. In this example, the observed rate of drug-related toxicity increases by 10% across all dose levels but the relationship with dose (as demonstrated by the slope of the curve) remains unchanged.

Synergy of dasatinib and anti-CTLA-4. Using murine GIST mouse, it was observed that treatment with the KIT-targeted dasatinib for 7 days alone or with chronic anti-CTLA-4 alone decreased tumor volume initially; however tumors rapidly re-grew. Mice treated with KIT-targeted TKI for 7 days and chronic anti-CTLA-4 blockade showed augmentation and durability of the initial response. KITV5880+ mice received dasatinib 15mg/kg i.p. bid (Bristol Myers Squibb) on days 1 through 7, with or without anti-CTLA-5 (BioXcell.) Mice were imaged at baseline and serially during therapy using MRI and volumetric analysis was done using Image K software. Anti-CTLA-4 dosing regimen 200 microgram of clone 9H10 i.p. on day 3, then 100 microgram on day 6, 9 and 12, followed by clone 9D (100 micrograms i.p. every 3 days thereafter.)

Supplementary Data from 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: A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic.Experimental Design: A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related RECIST criteria (irRC).Results: A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (n = 20) and other sarcomas (n = 8.) Dasatinib 70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3 mg/kg can be safely administered. Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia. No partial or complete responses were noted by RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi criteria, and 3 of 13 patients each had stable and progressive disease, respectively.Conclusions: Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination. This limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required. In the era of more modern and effective checkpoint inhibitors, next steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in combination with anti-PD-1 therapy. Clin Cancer Res; 23(12); 2972–80. ©2016 AACR.

Histograms of physician attribution (5-tier scale) of all grade {greater than or equal to}3 toxicities by toxicity category. On the attribution scale (x axis), 1 represents 'unrelated', 2 represents 'unlikely related', 3 represents 'possibly related', 4 represents 'probably related', and 5 represents 'definitely related'.

Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas.Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20–400 mg twice a day, days 1–7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort.Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2. Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response.Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702. Clin Cancer Res; 23(15); 4119–26. ©2017 AACR.

Supplementary Figure from Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma

Table of adverse events grade 1-4, at least possibly related to treatment. All G1-G4 at least possible related toxicity.

Purpose:We sought to determine the mechanism of an exceptional response in a patient diagnosed with a SMARCB1/INI1-negative chordoma treated with tazemetostat, an EZH2 inhibitor, and followed by radiotherapy.Patient and Methods: In an attempt to investigate the mechanism behind this apparent abscopal effect, we interrogated tumor tissues obtained over the clinical course. We utilized next-generation sequencing, standard IHC, and employed a novel methodology of multiplex immunofluorescence analysis.Results:We report an exceptional and durable response (2+ years) in a patient with SMARCB1-deleted, metastatic, poorly differentiated chordoma, a lethal disease with an overall survival of 6 months. The patient was treated for 4 weeks with tazemetostat, an EZH2 inhibitor, in a phase II clinical trial. At the time of progression she underwent radiation to the primary site and unexpectedly had a complete response at distant metastatic sites. We evaluated baseline and on-treatment tumor biopsies and demonstrate that tazemetostat resulted in pharmacodynamic inhibition of EZH2 as seen by decrease in histone trimethylation at H3K27. Tazemetostat resulted in a significant increase in intratumoral and stromal infiltration by proliferative (high Ki-67), CD8+ T cells, FoxP3+ regulatory T cells, and immune cells expressing checkpoint regulators PD-1 and LAG-3. These changes were pronounced in the stroma.Conclusions:These observations are the first demonstration in patient samples confirming that EZH2 inhibition can promote a sustained antitumor response that ultimately leads to T-cell exhaustion and checkpoint activation. This suggests that targeted alteration of the epigenetic landscape may sensitize some tumors to checkpoint inhibitors.

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.

Purpose Missing scores complicate analysis of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) because patients with and without missing scores may systematically differ. We focus on optimal analysis methods for incomplete PRO-CTCAE items, with application to two randomized, double-blind, placebo-controlled, phase III trials. Methods In Alliance A091105 and COMET-2, patients completed PRO-CTCAE items before randomization and several times post-randomization (N = 64 and 107, respectively). For each trial, we conducted between-arm comparisons on the PRO-CTCAE via complete-case two-sample t-tests, mixed modeling with contrast, and multiple imputation followed by two-sample t-tests. Because interest lies in whether CTCAE grades can inform missing PRO-CTCAE scores, we performed multiple imputation with and without CTCAE grades as auxiliary variables to assess the added benefit of including them in the imputation model relative to only including PRO-CTCAE scores across all cycles. Results PRO-CTCAE completion rates ranged from 100.0 to 71.4% and 100.0 to 77.1% across time in A091105 and COMET-2, respectively. In both trials, mixed modeling and multiple imputation provided the most similar estimates of the average treatment effects. Including CTCAE grades in the imputation model did not consistently narrow confidence intervals of the average treatment effects because correlations for the same PRO-CTCAE item between different cycles were generally stronger than correlations between each PRO-CTCAE item and its corresponding CTCAE grade at the same cycle. Conclusion For between-arm comparisons, mixed modeling and multiple imputation are informative techniques for handling missing PRO-CTCAE scores. CTCAE grades do not provide added benefit for informing missing PRO-CTCAE scores. ClinicalTrials.gov Identifiers: NCT02066181 (Alliance A091105); NCT01522443 (COMET-2).

Palmar and plantar fibromatosis are benign proliferative processes which present as a diffuse thickening or nodules of the hands and/or feet and may lead to flexion contractures, pain, and functional impairment known as Dupuytren and Ledderhose diseases, respectively. Current treatments are noncurative and associated with significant morbidity. Here, we report on the outcomes of 5 patients with advanced disease, no longer surgical candidates, treated with sorafenib. Sorafenib exhibited an expected safety profile. All 5 patients demonstrated objective responses as evaluated by a decrease in tumor size and/or tumor cellularity from baseline and all 5 patients reported subjective pain relief and/or functional improvement. Mechanistically, immunohistochemistry revealed patchy positivity for PDGFRβ, a known target of sorafenib. The outcomes of these 5 patients suggest the safety and efficacy of a relatively well-tolerated oral agent in the treatment of Dupuytren and Ledderhose diseases and suggest the need for future controlled studies.

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461 ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.