Frankel, Paul

11505 Background: Potentiation of chemotherapy, without increased toxicity, to improve outcome is an area of interest. Preclinical and clinical evidence shows simultaneous utilization of antiangiogenic agents and chemotherapy have a synergistic effect. We hypothesized that the dual targeting of VEGF and c-MET pathways with cabozantinib (CAB) would result in clinical benefit for patients with soft tissue sarcoma (STS) when combined with temozolomide (TMZ), an alkylating agent. Utilization of CAB/TMZ is anticipated to produce a synergistic antitumor effect worthwhile to explore in STS. Methods: A multicenter phase II study of CAB/TMZ in patients with unresectable/metastatic leiomyosarcoma (LMS) and other STS was conducted by the Midwest Sarcoma Trials Partnership. Age ≥ 18, adequate performance status, organ function, measurable disease (RECIST 1.1), and 0-5 prior chemotherapy regimens were required. CAB 40 mg PO daily plus TMZ 150-200 mg/m2 PO 1-5 days were given in 28-day cycles until disease progression or unacceptable toxicity. Patients enrolled in 2 cohorts: 1. Uterine and non-uterine LMS 2. Other STS. The first 14 subjects to be enrolled in the study in either cohort served as a safety lead in. The primary endpoint was progression-free rate (PFR) at 12 weeks for cohort 1. Secondary endpoints include overall response rate (ORR), clinical benefit rate, median progression-free survival (PFS), overall survival, and safety and tolerability. The exploratory endpoint was to estimate the correlation of PFR and OS to expression levels of VEGF, amongst others. A Simon 2-stage design was used. Results: A total of 42 patients were enrolled in Cohort 1, and 30 in Cohort 2, across 5 sites. For Cohort 1, median age was 59 years (range 35-86), 85.7% were non-Hispanic, 73.8% were female, 61.9% had ECOG of 0. The PFR at 12 weeks was 45.9% (for 37 evaluable patient) with a median PFS of 6.4 months (95% CI 4.6-6.7). Five PR were observed for an ORR of 13.5%. For Cohort 2, median age was 63 (20-86), 83.3% were non-Hispanic, 36.7% were female, 53.3% had ECOG of 0. The PFR at 12 weeks was 50% (for 28 evaluable patients) with a median PFS of 3.2 months (95% CI 1.4-4.6). One PR was observed. Reported grade 3-4 adverse events attributed to one or both intervention drugs affecting ≥10% of patients (n = 70) included hypertension (10%), decreased neutrophils (18.7%), decreased platelets (31%). Conclusions: The combination therapy of CAB/TMZ in patients with unresectable or metastatic LMS exceeded its primary endpoint with a PFR at 12 weeks > 39%. The PFS of 6.4 months in Cohort 1 exceeds rates achieved with second line tyrosine kinase inhibitors (TKIs) and alkylators in LMS patients. Treatment was feasible and did not reveal any previously unreported toxicities. The combination with CAB with TMZ demonstrated meaningful clinical benefit and is worth further exploration in LMS. Clinical trial information: NCT04200443 .

5554 Background: Epithelial ovarian cancer (EOC) is characterized by chemoresistant recurrences primarily confined to the intraperitoneal cavity, frequently leading to malignant small bowel obstructions. Intraperitoneal (IP) chemotherapy has been incorporated in EOC, but only in the first-line setting. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel IP drug delivery method that optimizes tissue penetration depth and drug distribution, to treat recurrent peritoneal malignancies. Recent trials outside the U.S. demonstrated partial to stable response following PIPAC in recurrent EOC. To date, no clinical trials have been completed investigating the role of PIPAC in EOC in the United States. Methods: We performed a multicenter prospective phase I trial using IP cisplatin 10.5 mg/m2 and doxorubicin 2.1 mg/m2 via PIPAC at 6-week intervals. Patients were eligible if they had recurrent disease with peritoneal metastasis; extraperitoneal metastasis was allowed. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included progression free survival, PCI scoring, RECIST measurements, and quality of life (QoL). The patients with gastric and uterine cancers’ toxicity data were used but given inherent prognostic differences the treatment efficacy for these patients were not used in this analysis. Adverse event (AE) monitoring was graded using CTCAE spanning 18 weeks. Following completion of treatment (³2 PIPACs) patients were followed up every 12 weeks. QoL was measured using patient-reported assessments at 0, 6, 12, and 18 weeks. Baseline demographics were summarized. Mean change in PCI was calculated between cycle (C) 1 and 2, and cycle 2 and 3. Toxicities attributed to the surgery or PIPAC were reported with highest grade for each patient. Results: Nine heavily pretreated, recurrent patients were enrolled in the trial: 7 with platinum-resistant recurrent EOC, 1 with uterine cancer, and 1 with gastric cancer. PIPAC completion rate was 71.4%. Median age of participants was 65 years. Median prior lines of chemotherapy were 4 (range 2 - 10). No surgical complications occurred in the cohort. Two patients came off study: one for G3 abdominal pain and the other for G3 anorexia. For the EOC cohort, the median PCI reduction was -1.4% (C1 to C2) and -2.8% (C1 to C3). One low-grade serous EOC patient demonstrated a partial response based on RECIST criteria and received 6 cycles. Two EOC patients showed an initial response based on PCI reduction, but progressed following Cycle 2. Overall, QoL was stable. Conclusions: PIPAC with cisplatin/doxorubicin in platinum-resistant ovarian cancer is well tolerated. Intraperitoneal responses were seen in a subset of low-grade serous ovarian cancer patients, which may warrant further study. Heavily pretreated, platinum-resistant high-grade EOC patients derived limited intraperitoneal control from PIPAC monotherapy. Clinical trial information: NCT04329494 .

Abstract Objectives Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC. Methods This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7–25 mg/m 2 ) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total. Results The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics. Conclusions This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

125 Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is being evaluated as a novel minimally invasive palliative treatment of peritoneal metastases (PM). Prior studies have established the feasibility and safety of repeated PIPAC treatments in gastrointestinal and gynecologic cancers. The goal of the present phase 1 trial was to establish the safety and feasibility of PIPAC oxaliplatin in a highly chemotherapy refractory colorectal and appendiceal cancer patient population. Methods: Patients with biopsy-proven peritoneal metastases from colorectal or appendiceal cancer underwent up to three PIPAC treatments using oxaliplatin (92 mg/m2) with a six-week interval at two academic centers. Patients with bowel obstruction, extra-peritoneal metastases, or poor performance status (ECOG>2) were excluded. PIPAC was nebulized over 5 min with a 30 min aerosol dwell time. Apart from the first PIPAC cycle, the patients also received a sensitizing dose of 5FU/LV (400mg/m2) within 24 hours of the procedure. Primary end point was safety as assessed by dose limiting toxicities within 6 weeks of the first PIPAC. Secondary endpoints included safety with the addition of 5FU/LV, efficacy, surgical morbidity, technical failure rate, progression-free and overall survival, pharmacokinetics (PK), and quality of life assessment. Results: A total of 8 patients were included: 5 colorectal; and 3 appendiceal. Median number of prior chemotherapy cycles was 2 (Interquartile range – IQR; 1.5-3.5). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median time from diagnosis to PIPAC was 16 months (IQR; 5.6, 17.5) and Peritoneal Carcinomatosis Index was 29 (IQR; 20.5, 31.5). Five (62.5%) patients completed 3 PIPAC cycles while in 3 (37.5%) patients PIPAC was discontinued due to disease progression within the peritoneal cavity. No surgical complication or dose limiting toxicity was observed. Only one patient developed grade 3 treatment-related toxicity after first PIPAC (anemia), and another patient after second PIPAC (abdominal pain and anemia). At the completion of PIPAC treatment 5 patients had stable disease and 3 had disease progression. Pharmacokinetic, histologic response and preliminary survival data will be presented at the meeting. Conclusions: PIPAC with oxaliplatin is safe and feasible in a highly chemotherapy refractory cohort of appendiceal and colorectal carcinomatosis patients with or without sensitizing 5-FU/ LV. Clinical trial information: NCT04329494.

Background. This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable, pulmonary metastatic osteosarcoma. Patients and Methods. Patients with pulmonary metastatic osteosarcoma unresponsive to chemotherapy were eligible. Patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessment 1 month prior to and after initiation of treatment to calculate tumor doubling time and after every even numbered cycle. The primary endpoints were progression-free survival at 4 months, concomitant with a demonstrated 30% increase in tumor doubling time relative to the pretreatment growth rate. Results. 12 patients (7 female) were enrolled. The study was terminated prematurely due to withdrawal of financial support by the sponsor. 8 subjects were eligible for the primary analysis, whereas 4 patients were in a predefined exploratory “slow-growing” cohort. In the “fast-growing” cohort, 3 of the 8 patients (37.5%) eligible for first-stage analysis were deemed “success” by the preplanned criteria, adequate to proceed to second-stage accrual. In addition, 1 of the 4 patients in the “slow-growing” cohort experienced a partial remission. Grade 1-2 diarrhea was the most common adverse event, and grade 3 events were infrequent. Conclusion. This study illustrates a novel method of demonstrating positive drug activity in osteosarcoma by increasing tumor doubling time, and this is further supported by a partial response in a patient with “slow-growing” disease. This trial is registered with NCT01759303.

1024 Background: The combination of platinum agents and PARP inhibitors may benefit patients (pts) with BRCA-associated metastatic breast cancer (MBC). We report on the response and clinical benefit rates when combining the PARP inhibitor veliparib (V) and carboplatin (carb) in a phase I trial. Methods: BRCA carriers with MBC were eligible. Carb starting at an AUC of 6 was given IV in 21-day cycles (C) and V was given orally twice daily (BID) at dose levels (L) L1 through L5. Results: Twenty-eight pts (26 eligible) carrying BRCA1 (12) or BRCA2 (15), or both (1) mutations were accrued between June 2010 and June 2012. The median age (32-66) was 45 years. The number (#) of prior chemotherapy regimens given for MBC was 1 (0-5); 70% of BCs were ER+, and 7% were HER2+. The schema, dose limiting toxicities (DLT) during C 1, median # of Cs on trial, and maximum tolerated dose (MTD) are shown. There were 3 (12%) complete and 9 (35%) partial responses (PR). Unconfirmed PR or stable MBC (median duration: 8 months [6-10+]) were seen in 7 pts (27%); the clinical benefit rate was74%. The median progression-free survival (PFS) is 7.8 months (95% CI 7.3-9.5). The pt with Fallopian tube cancer had a CR. DLTs with C 1 were seen in 2/6 evaluable pts at L1 (1 pt w/grade 3 hyponatremia and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to de-escalation of carb. At L2, 1 pt had grade 4 PLT. At L5, 1 pt had grade 4 PLT, and 2 pts grade 3 PLT (1 pt also experienced grade 4 granulocytopenia [ANC]), defining the MTD at carb AUC 5 and V 150 mg BID (L4). Dose delays and/or dose adjustments due to grade ≥ 2 toxicities for ANC or PLT were seen during the first 3 Cs at L1 (100%), L2 (50 %), L3 (67%), L4 (83 %), and at L5 (67%). Conclusions: The combination of carb and V is active, and is associated with substantial clinical benefit rate and managable hematologic toxicities in BRCA carriers with MBC. Further definition of the role of V is warranted. [Table: see text]

Background This single‐arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. Methods Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28‐day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). Results Forty‐seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%‐58%), which was superior to the null hypothesis rate of 30%, but the 2‐sided P value (exact test) was .09 (1‐sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3‐35.0 months), and the median progression‐free survival was 7.9 months (95% CI, 3.7‐12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. Conclusions This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.