Chen, Yen‐Lin

AbstractBackgroundThis was a single‐arm, phase 2 clinical trial of Bavarian Nordic (BN)‐Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression‐free survival (PFS), and safety of the combination in chordoma.MethodsA total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara‐Bavarian Nordic (MVA‐BN)‐Brachyury and one vaccine dose of fowlpox virus (FPV)‐Brachyury before RT. After RT, booster vaccinations were given with FPV‐Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients.ResultsTwo of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6–20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4–90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7–25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study.ConclusionsThis trial confirms the safety of BN‐Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine‐based study in chordoma, an ultra‐rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867 ). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B ( P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B ( P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

AbstractBackground and ObjectivesThe impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/− chemotherapy for soft tissue sarcoma.MethodsWound complications were evaluated on dose‐finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/− pazopanib, +/− ifosfamide/doxorubicin (ID) for sarcoma therapy.ResultsOf 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites.ConclusionThe addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

11504 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity in advanced soft tissue sarcoma. ARST1321 was a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) following preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive body wall/extremity NRSTS. Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary analysis of the study, we now report the outcome data for this cohort. Methods: ARST1321 was a jointly designed COG and NRG Oncology study open to enrollment July 2014-October 2018. Eligible adult (≥18 years) and pediatric (< 18 years) patients with newly-diagnosed unresected body wall/extremity NRSTS were enrolled into the Chemotherapy Cohort (> 5 cm, FNCLCC grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib (< 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then further chemotherapy to week 25. Results: Eighty-five eligible patients were enrolled in the Chemotherapy Cohort and randomized to receive or not receive pazopanib. Median age 22.1 years (range: 5.7-64.2 years); 30 patients < 18 years. Most common histologies were synovial sarcoma (n = 42) and undifferentiated pleomorphic sarcoma (n = 19). As of December 31, 2021, at a median survivor follow-up of 3.3 years (range: 0.1 – 5.8 years), the 3-year event-free survival (EFS) for all patients in the intent-to-treat analysis was 52.5% (95% CI: 34.8%-70.2%) for Regimen A and 50.6% (32%-69.2%) for Regimen B (p = 0.8677); 3-year overall survival (OS) was 75.7% (59.7%-91.7%) for Regimen A and 65.4% (48.1%-82.7%) for Regimen B (p = 0.1919). Conclusions: Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk body wall/extremity NRSTS, outcomes were not statistically significantly different between the two regimens. Pathologic response could be a TKI-related phenomenon and may not be a good surrogate marker of outcome in future studies. Clinical trial information: NCT02180867.

11550 Background: RPS often have local recurrence (LR) after surgery. Preoperative radiation (RT) to 50.4 Gy can reduce LR risk but is not uniformly effective, especially after (+) margin resections. Therefore, we conducted a multi-institutional, prospective Phase II study to assess efficacy and tolerability of preop IMPT with selective dose escalation to 63 GyRBE to the posterior RPS margin (clinical target volume [CTV] 2) at high risk for (+) margins to further reduce the risk of LR. This dose was tolerable in a prior phase I study (DeLaney T et al, 2017, PMID:28740917). Methods: Primary RPS patients (pts) >18 years received preop IMPT, 50.4 GyRBE in 28 fractions (fx) of 1.8 GyRBE to CTV1 (tumor plus adjacent tissue at risk of subclinical disease) with SIB to CTV2 to 63.0 GyRBE in 28 fx of 2.25 GyRBE. Pts with high-grade tumors could get chemotherapy(CTX) prior to IMPT. To avoid treatment delay, 11 fx of IMRT x-rays could be substituted for IMPT. Pts had restaging and surgery 4-8 weeks after IMPT. Primary study endpoint was local tumor control. Secondary endpoints included clinical and pathologic response, surgical margin status, and disease-free and overall survival. Results: We accrued 60 pts from January 2016 to February 2021. Histology: 35 liposarcoma(LPS) (19 dediff and 16 well diff), 22 leiomyosarcoma(LMS), and 3 undifferentiated pleomorphic sarcoma. IMPT was delivered per protocol in all pts. 51 pts have had surgery, 5 are awaiting surgery, and 4 had no surgery due to metastases(DM) on preop imaging. 22 pts had (+) margins. 2 pts had > 75% necrosis. With 23-month median (range 1-52 months) follow-up after start of RT, there were two LRs. A dediff LPS pt had a well diff LPS LR 26 months postop, resected, and is disease-free. A renal vein/IVC LMS pt treated with CTX and IMPT had LR and DM 4 months postop and died from disease. Surgical Clavien-Dindo morbidity scores: 0(21), 1(9), 2(8), 3a (4), 3b(4), 4a(2), 4(b)1, 5(2); the periop deaths were from sepsis(pneumonia) and duodenal ulcer. The grade 3-4 periop morbidity included abscess(3), treated by catheter(2) or operative(1) drainage, prolonged hospital stays (2 pts with IVC LMS), small bowel obstruction (1), and late sigmoid colon anastomotic failure (1). Readmissions for lymphopenia(1), pneumoperitoneum (1), and volume overload (1). One late neuropathy was seen in a Type II diabetic pt with transient postop weakness after femoral nerve dissection who later had significant lower extremity weakness 3.75 years postop. Study was amended to reduce IMPT dose in diabetic pts. Conclusions: Preoperative IMPT with selective dose escalation to 63 GyRBE to the high risk posterior RPS margin is feasible. Early local control results with this approach appear promising. Some peri-operative morbidity was noted but appears to be in the expected range for RPS resections. Clinical trial information: NCT01659203.

e19214 Background: ARST1321(PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NCT02180867) was the first National Clinical Trials Network (NCTN) study co-developed by pediatric (COG) and adult (NRG Oncology) consortia anticipating enrollment of adolescent and young adult (AYA) cancer patients. ARST1321 had two treatment cohorts, enrolling patients ≥ 2 years of age to either chemotherapy (C) (chemoradiation ± pazopanib) or non-chemotherapy (NC) (radiation ± pazopanib) arms. It was anticipated adults would contribute the majority of enrollments on the NC arm based on prior enrollment patterns. While the C arm accrued as anticipated (with high enrollment of adults and children), the NC arm had low enrollment leading to premature closure. We report on AYA accrual (defined as 15-39 years) to the NC arm and a survey aiming to identify barriers to enrolling AYA patients onto ARST1321. Methods: Our survey was emailed to 161 adult, surgical, and radiation oncologists at large sarcoma centers. A link was sent to an online questionnaire via SurveyMonkey Inc. and responses were reviewed on their platform. Results: 33 patients enrolled on the ARST1321 NC arm, of which 24% were AYA. 25% of AYA enrollments were from non-COG adult cooperative groups. This trial arm was closed in October 2017 after 3.25 years of accrual below anticipated rates. The survey response rate was 31% with a 70% completion rate. Almost half of respondents were medical oncologists with most seeing 50-200 new sarcoma cases/year at an academic institution and 30% in a pediatric environment (divided equally between radiation and surgical oncologists). 70% of respondents have a joint collaboration with their pediatric oncology team with 23% having a joint clinic. 70% of respondents’ sites opened ARST1321 and anticipated 1-5 patients would be eligible for the NC cohort. However, 42% of respondents’ sites had zero patients enrolled on that arm. The most common reasons for not opening the study and/or not enrolling patients on the NC arm included: lack of interest, disagreement with the therapy, lack of a site investigator, premature study closure, patient/family decision, competing trials, insufficient reimbursement, and regulatory delays. Conclusions: Our survey highlights multiple barriers to enrollment of AYA onto cross-NCTN consortia clinical trials spanning the age spectrum. The information obtained will help inform investigators aiming to effectively design, enroll, and conduct similar trial efforts for AYA in the future.

11070 Background: Pazopanib is a tyrosine kinase inhibitor approved globally for advanced soft tissue sarcomas. The dose finding phase of this cooperative group trial assessed the dose limiting toxicities (DLT) and the maximally tolerated dose (MTD) of adding pazopanib to neoadjuvant chemoradiation or radiation therapy in children and adults with unresected intermediate/high-risk trunk and extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Methods: ARST1321, a jointly designed intergroup study lead by Children's Oncology Group and NRG Oncology opened for enrollment in July 2014. Eligible adult and pediatric patients with newly diagnosed, unresected trunk/extremity NRSTS with plans for primary tumor resection were enrolled into either the Chemotherapy Cohort (those with chemosensitive NRSTS > 5 cm, grade 3, including all synovial sarcoma) or the Non-Chemotherapy Cohort (those with chemotherapy insensitive NRSTS of any size, grade 2/3, or any chemosensitive NRSTS for whom no chemotherapy was planned per discretion of patients and treatment teams). In the Chemotherapy Cohort, pazopanib was given with ifosfamide (7.5 grams/m2) and doxorubicin (75 mg/m2) plus 45 Gy preoperative RT starting after cycle 2. Primary tumor was resected at week 13, followed by chemotherapy and pazopanib to week 25. In the Non-Chemotherapy Cohort, pazopanib was given with 50 Gy preoperative RT, primary tumor was resected at week 10, and pazopanib continued to week 25. Feasibility was assessed through week 6 of therapy to determine pazopanib dose escalation/de-escalation based on DLT, total doses of pazopanib, and overall adverse event profile. Results: In the Chemotherapy Cohort, MTD was reached at Dose Level 1 (350 mg/m2 peds; 600 mg adults) with two DLTs (1 grade 3 ALT rise, 1 intolerability to therapy) in 10 patients. In the Non-Chemotherapy Cohort, 11 patients enrolled at Dose Level 1 (350 mg/m2 peds; 600 mg adults) without any observed DLTs and all received ≥75% of prescribed total pazopanib dose; MTD was reached at Dose Level 2 (450 mg/m2 peds; 800 mg adults) with 2 DLTs in ten patients enrolled (1 grade 3 dermatitis and 1 intolerability to therapy) and 9/10 receiving ≥75% of full dose. Conclusions: Pazopanib in combination with chemoradiation or radiation therapy alone was found to be safe in children and adults with NRSTS. Following this finding, ARST1321 opened in both arms using the newly determined pazopanib MTDs. Clinical trial information: NCT02180867.

11002 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor with activity in advanced soft tissue sarcoma. ARST1321 is a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) of preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive NRSTS. Methods: ARST1321 is a jointly designed COG and NRG Oncology study opened to enrollment in July 2014. Eligible adult (≥18 years) and pediatric ( < 18 years) patients with unresected, newly diagnosed truncal/extremity NRSTS were enrolled into the Chemotherapy Cohort ( > 5 cm, grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib ( < 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then adjuvant chemotherapy. Results: As of June 30, 2018, 81 eligible patients were enrolled and randomized. Week 13 response is available for 42 patients (60% of expected information). The rate of ≥ 90% pathologic necrosis was 58.3% for Regimen A and 22.2% for Regimen B. Based on the significance level of 0.081 (for the second efficacy analysis with overall one-sided significance level of 0.20, power of 0.80, and O’Brien-Fleming-type cumulative error spending function), the 83.8% confidence interval for the difference was between 16.5% and 55.8%. At this predetermined interim analysis, the efficacy bound was crossed indicating that Regimen A is more efficacious than Regimen B. Given these findings, enrollment was stopped. Grade 3/4 toxicities were 73.8% for Regimen A and 29% for Regimen B with neutropenia, thrombocytopenia and febrile neutropenia being the most common toxicities. Conclusions: The rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk NRSTS. The comparison of survival outcomes requires longer follow-up. Clinical trial information: NCT02180867.