Simon's Optimal Two-stage Design Research Articles

Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.

TPS4625 Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952 .

Neoadjuvant dalpiciclib, exemestane, and goserelin in premenopausal women with HR-positive, HER2-negative breast cancer: A prospective, multicenter, randomized two-group, non-controlled phase 2 clinical trial.

TPS625 Background: The combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has significantly improved progression-free survival and overall survival in patients with HR-positive, HER2-negative advanced breast cancer (BC), revolutionizing the treatment landscape. However, previous CDK4/6i neoadjuvant studies have predominantly focused on postmenopausal populations, leaving a gap in preoperative treatment for early HR-positive, HER2-negative premenopausal BC patients. Therefore, the present trial is conducted to investigate the efficacy of dalpiciclib, exemestane and goserelin as neoadjuvant therapy in premenopausal women with HR-positive, HER2-negative BC. Methods: This is a multicenter, randomized two-group, non-controlled phase 2 clinical trial. Key eligibility criteria include: Patients aged 18 years or older with no prior treatment, an ECOG performance status of 0-1, at least 1 measurable lesion, and clinical stage II-III HR-positive, HER2-negative premenopausal invasive BC. Initially, all enrolled patients will receive two cycles of treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC). Subsequently, patients with complete response (CR) or partial response (PR) will receive an additional four cycles of TAC, whereas patients with progressive disease (PD) will undergo surgery or treatment options decided upon by the investigators. Those with stable disease (SD) will be randomly assigned 1:1 to either an experimental group receiving 16 weeks of dalpiciclib, exemestane, and goserelin (dalpiciclib: 125 mg daily for 21 days followed by 7 days off, exemestane: 25 mg daily for 28 days, goserelin: 3.6 mg every 28 days) or a standard chemotherapy group receiving four more cycles of TAC. Treatment response is assessed according to RECIST 1.1 criteria. Surgery will be performed after completion of the planned neoadjuvant treatment, followed by radiation therapy and systemic treatment according to local guidelines or the investigators' choices. The study's primary endpoint is the objective response rate (ORR) of the experimental group. Secondary endpoints include the ORR, residual cancer burden, preoperative endocrine prognostic index, event-free survival, and safety of both. Using Simon's two-stage optimal design and assuming a 40% response rate as desirable in the experimental group, at least 13 responses among a total of 43 patients were required to meet the primary endpoint. The trial will be terminated if fewer than 3 patients respond in the first stage. Considering an 80% SD rate post two neoadjuvant TAC cycles and a 10% attrition, the sample size was ultimately set at 119. The trial is actively recruiting. Clinical trial information: NCT06009627 .

Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) for metastatic urothelial carcinoma (mUC) treatment-experienced (DAD) and with pembrolizumab (P) in treatment naïve UC (DAD-IO).

TPS4618 Background: In the DAD study (NCT04724018) the combination of SG+EV demonstrated favorable safety determining a maximum tolerated dose of 10 mg/kg and 1.25 mg/kg IV D1,8 every 21 days along with encouraging efficacy in treatment resistant mUC as evidenced by an objective response rate (ORR) of 70% in 23 evaluable patients. Given cumulative toxicities and efficacy across dose levels, the recommended phase 2 dose was SG 7.5 mg/kg and EV 1.25 mg/kg D1,8 of 21-day cycle. As EV+P is now a standard of care for front line urothelial carcinoma, NCT04724018 was amended to include 2 cohorts of distinct patient populations; one expanding SG+EV (DAD) and a second exploring the SG+EV+P (DAD-IO) combination. Methods: In DAD cohort, patients with mUC progressing on platinum and immunotherapy or on one line of therapy receive SG 7.5 mg/kg + EV 1.25 mg/kg intravenously (IV) on day(D)s 1 and 8 every 3 weeks (1 cycle) until progression or intolerable toxicities. In DAD-IO cohort, patients with treatment naïve mUC are given SG 7.5 mg/kg+EV 1.25 mg/kg IV D1, 8 of a 21-day cycle with P 200 mg every 3 weeks or 400 mg every 6 weeks per investigator discretion. In both cohorts, prophylactic granulocyte colony stimulating factor (GCSF) support is given per supportive care guidelines with cycle 1. Following first dose on trial, SG and EV can be reduced and held independently for toxicity with reductions of SG to 5 mg/kg, and EV to 1, 0.75 and 0.5 mg/kg. P dose reductions are not allowed but can be held as needed for immune related adverse events. Laboratory evaluation is performed on days 1 and 8 every cycle. Imaging is performed at baseline and every 6 weeks for the first 4 cycles followed by every 9 weeks thereafter. In both cohorts, the primary endpoint is RECIST 1.1 ORR with secondary endpoints being progression free survival, overall survival, and safety. DAD aims to enroll 41 eligible patients, assuming an ORR of 65% for EV+SG, to detect a 25% improvement with over 90% power at a one-sided type I error rate of 0.05 using a single-stage exact one-sample binomial design; ³ 23 responses would rule out a null of 40% ORR. DAD-IO plans to enroll 41 eligible patients, assuming an ORR of 75% for SG+EV+P to detect a 20% improvement with 90% power at a one-sided type I error rate 0.09 based on a Simon optimal two-stage design. If ³ 11 responses are observed in the first 18 patients, an additional 23 patients will be enrolled. At least 27 responses among a total of 41 will be needed to confirm its efficacy. The study includes a 12-patient safety lead in using a Bayesian toxicity monitoring. If ≤2 dose limiting toxicities (DLTs) occur in the first 6 patients, the next 6 are enrolled. The study halts if ≥5 DLTs occur among 12 evaluable patients. Clinical trial information: NCT04724018 . [Table: see text]

Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE

Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. Patients (n= 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n= 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage2. NCT03812796 (registered 23rd January 2019).

A modified triplet combination of docetaxel, oxaliplatin, and fluorouracil for gastric cancer (GC) with peritoneal carcinomatosis (PC) and inoperable malignant bowel obstruction (MBO): A multi-center, non-randomized, three-cohort, phase II trial (Zhen Jing).

TPS426 Background: For GC, PC is ranked as the most common in relapse and the second common in metastasis. MBO is a frequent and preterminal complication of PC, which has been reported to have a poor overall survival (OS) of only 3 months without effective treatment. Medical therapy of gastroenteric drainage and symptomatic drugs is the cornerstone management for MBO, just alleviating symptoms. Interventional therapy and surgery are effective but indicated in limited patients (pts) with strict selection. Chemotherapy is the mainstay treatment for metastatic GC but its role in MBO is poorly defined. Only a few retrospective studies are available, showing conflicting results on obstruction clearance (OC) and OS. Methods: We are conducting the Zhen Jing trial in five Chinese centers to investigate the tolerability and efficacy of a dose-sense regimen of docetaxel, oxaliplatin and fluorouracil in MBO from GC. Cohort A is for pts in first-line setting. Cohort B is for second-line setting. Cohort C is for pts who have failed to two or more regimens. Eligible pts will receive the same experimental regimen every 28 days: docetaxel 25 mg/m2 on days 1, 8, 15; oxaliplatin 85 mg/m2 on days 1, 15; fluorouracil 1200 mg/m2 24-hour infusion on days 1, 8, 15. A Simon's two-stage optimal design is applied (table below). The primary endpoint is 60-day OC rate. Secondary endpoints are 30-day OC rate, time to OC, OC duration, safety, overall survival and quality of life. Till July 2023, a total of 34 pts has been enrolled (16 in cohort A, 9 in cohort B, 9 in cohort C). Inclusion Criteria: 18-75 years old; Eastern Cooperative Oncology Group performance status ≤ 3; adenocarcinoma of stomach or gastroesophageal junction; peritoneal carcinomatosis established by imaging data or pathological evidence; MBO below the Treitz ligament based on clinical grounds or radiological findings; inappropriate for operation judged independently by two surgeons; written informed consent. Exclusion Criteria: Treated by a combination regimen containing all the study drugs; allergy to any of the study drugs; HER-2 gene overexpression; high microsatellite instability or mismatch repair deficiency; strangulated obstruction; active gastrointestinal bleeding; uncontrolled active infection; unstable heart diseases; severe lung diseases; central nervous system diseases; concomitant cerebral or meningeal metastasis; surgery or stent are required. Clinical trial information: NCT04840264 . [Table: see text]

Infusional fluorouracil and weekly docetaxel as first-line therapy for gastric cancer with bone marrow metastasis and disseminated intravascular coagulation: A multi-center, phase II trial (Zhen Long).

337 Background: Gastric cancer (GC) with bone marrow metastasis (BMM) and disseminated intravascular coagulation (DIC) constitute a highly aggressive GC (HAGC) sub-type with distinctive features. The prognosis is poor and most HAGC patients die in weeks without effective treatment. Undue concerns about the myelosuppression mitigate against the application of cytotoxics in HAGC which is characterized by thrombocytopenia. Retrospective analysis showed low dose chemotherapy might relieve the DIC and bring with survival benefit but the standard of care (SOC) has not yet been established without a prospective study available. We completed a multi-center phase II trial evaluating the safety and efficacy of infusional fluorouracil and weekly docetaxel as first-line (1L) treatment for HAGC. Methods: This was a single-arm trial. A Simon's two-stage optimal design was applied. Eligible cases were: 18-75 years old, histologically confirmed GC, established BMM, overt DIC, platelet ≤ 50*109/L and Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 3. Fluorouracil 200mg/m2/d continuous infusion on days 1-21 and docetaxel 25mg/m2/d on days 1, 8, 15 were given every four weeks. Hematological response (HeR) was defined as the platelet restored to normal range. The primary end point was HeR rate. Secondary end points were time to HeR (TTHeR), one month mortality (OMM), overall survival (OS), adverse events (AEs) and quality of life (QoL). Results: From Jan 2021 to Sep 2022, 24 HAGC cases from three Chinese centers were enrolled (details shown in table below). 20 HeRs were achieved and the HeR rate was 83.3%. Median TTHeR was 13 days and OMM was 12.5%. Till the data cut-off date (Jul 31, 2023), 3 patients were still alive with a median follow-up of 403 days. The median OS was 242 days. Totally, twelve Grade 3 AEs were recorded in 7 (29.2%) patients, among which stomatitis (4, 16.7%) and aminotransferase elevation (3, 12.5%) were the most frequent. No drug-related grade 4 or 5 AEs were observed. QoL outcomes were significantly improved both during and after the treatment. Conclusions: Anti-cancer treatment is the key point to control DIC of HAGC. The Zhen Long regimen was well tolerated and showed promising efficacy in the 1L setting. It should be considered as the SOC in current practice, but further randomized trials are still needed. Clinical trial information: NCT04547153 . [Table: see text]

Anti-PD-1 Antibody (Sintilimab) Plus Decitabine As First Line Treatment for Patients with Higher-Risk Myelodysplastic Syndrome (MDS): Primary Results from a Single-Arm,Open-Label,Phase II Study

Background: Hypomethylating agents (HMAs) are the preferred treatment for untreated patients with higher-risk Myelodysplastic Syndrome (MDS). However, the survival rate of patients after HMA treatment remains poor. Studies have shown that HMAs upregulate the expression of PD-1/PD-L1 in MDS patients, making the combination of HMAs with PD-1 antibodies a compelling approach for MDS treatment. Consequently, we conducted this single-arm, open-label clinical trial (ChiCTR2100044393) to assess the safety and efficacy of sintilimab in combination with decitabine for patients with higher-risk MDS. Methods: Adult patients with higher-risk MDS, according to the IPSS-R, were eligible for enrollment in this study. The treatment regimen consisted of daily intravenous administration of decitabine at a dose of 20mg/m 2 for 5 consecutive days, along with intravenous administration of sintilimab at 200mg on the first and 22nd day of a 42-day treatment cycle. Treatment continued until disease progression, death, unacceptable toxicity, withdrawal of consent, or other protocol-defined reasons, with a maximum of 8 cycles allowed. The primary endpoint of this study was the overall response rate (ORR). To determine the sample size, we utilized Simon's optimal two-stage design. Secondary endpoints included the assessment of safety and various survival outcomes. Additionally, we investigated the relationship between the expression levels of immune checkpoints and the efficacy of the combination therapy and other potential biomarkers through genomic profiling. Results: As of the data cut-off on June 16, 2023, 53 patients were enrolled, with a median follow-up time of 14 months, and 52 patients were eligible for response evaluation. The median age of patients was 65 years (range 19-83), other characteristics were summarized in Table 1.The ORR was 76.9%, and 15 patients achieved complete response (CR), 13 marrow complete response(mCR),7 mCR+ hematologic improvement(HI), and 5 HI. Among the 40 responders, six patients (4 with CR and 2 with mCR) underwent allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) has not reached, and the median event-free survival (EFS) was 16 months. The 24-month OS and EFS rates were 54.8% (95%CI: 39.5-76.2) and 46.2% (95%CI: 31.2-68.3), respectively. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) reported in 10% or more of the patients were febrile neutropenia (67.9%) and pulmonary infection (20.8%). A total of 17 patients (32.1%) experienced immune-related adverse events (irAEs), with the most common irAEs being rash (17.0%), thyroid dysfunction (9.4%), and pneumonia (7.5%), all resolved after glucocorticoid treatment. Regarding genetic mutations, the most frequently mutated genes were ASXL1 (34.0%), RUNX1 (30.2%), TET2 (17.0%), and U2AF1 (17.0%). Conclusion: To the best of our knowledge, this is the first study evaluating the efficacy and safety of the combination therapy with sintilimab and decitabine in previously untreated patients with higher-risk MDS. This regimen showed an encouraging anti-tumor activity with a manageable safety profile.

Efficacy of sequential chemoradiotherapy combined with toripalimab in de novo metastatic nasopharyngeal carcinoma: A phase II trial

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3months after radiotherapy is 81.8% (22.7% complete response, n= 5; 59.1% partial response, n= 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.

Brentuximab Vedotin‐Nivolumab alone and then with Rituximab‐Cyclophosphamide‐Doxorubicin‐Prednisone as Frontline Therapy of Primary Mediastinal Large B‐cell Lymphoma

Introduction: Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma and affects primarily young adults. PMBCL shares several features with classic Hodgkin lymphoma, such as 9p24.1 amplification, increased programmed cell death protein 1 (PD-1) ligand, and CD30 expression. The trial CheckMate-436 treated relapsed/refractory (rr) PMBCL patients with nivolumab (antibody that binds to PD-1) and brentuximab vedotin ((BV) anti-CD30 antibody-drug conjugate), who showed an overall response rate (ORR) of 73% and complete response rate (CRR) of 43% (Zinzani et al. JCO 2019). Although most PMBL patients can be cured with frontline chemoimmunotherapy (CIT) with or without radiotherapy (XRT), the outcome of patients having rr-PMBCL is generally unfavorable. The discovery of new frontline regimens represents an unmet need for PMBL patients. We hypothesize that BV+Nivolumab will show ORR in frontline therapy at least as high as in the rr setting, may avoid chemoresistance, could deescalate the intensity of CIT, and alleviate the need for consolidative XRT. Methods: We are conducting a phase II, open-label, single-center clinical trial NCT04745949 combining BV-Nivolumab alone and then combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for patients with previously untreated PMBL. Patients 18 years or older with previously untreated PMBL, stage I to stage IV disease are eligible. However, patients previously treated with up to one cycle of standard-of-care therapy are eligible. Patients will receive BV 1.8 mg/Kg IV and Nivolumab 240 mg flat dose IV day 1 for cycles 1 and 2, in a 21-day cycle. During cycles 3 and 4, R-CHP will be added to BV-Nivolumab. Patients who have achieved complete response (CR) at PET/CT before cycle 5 will receive 2 more cycles of BV-Nivolumab+R-CHP (cycle 5 and 6) and BV-Nivolumab only for cycles 7 and 8 (A). In case of CR on PET/CT after cycle 8, therapy will be considered completed. Patients in PR on PET/CT before cycle 5 will receive 4 more cycles of BV-Nivolumab+R-CHP (cycles 5–8 (B)). The primary endpoint is CRR at the end of therapy (EOT). The maximum sample size for the PMBL cohort is 40 patients, with a target CRR at EOT of 70%. The null hypothesis is that the true CRR at EOT is 50%, and the alternative hypothesis is that the true CRR at EOT is 70%. The Simon's optimal two-stage design controls the one-sided type I error rate at 0.06 and yields the power of 0.8. The secondary endpoints will include the response rate of BV-Nivolumab+R-CHP at the end of the immune lead-in, landmark survival outcomes, safety, and patient-reported outcome. Exploratory analyses include assessing molecular response by sequencing cell-free DNA and multiplex immunofluorescence to analyze the tumor microenvironment. The research was funded by: Seagen, BMS (drug support only) Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract R. E. Steiner Research funding: Seagen, BMS, GSK, Rafael Pharmaceuticals P. Strati Consultant or advisory role Roche-Genentech, Kite-Gilead, Hutchinson MediPharma, Astrazeneca-Acerta, ADC Therapeutics, Sobi and TG Therapeutics Research funding: Astrazeneca-Acerta, ALX Oncology and ADC Therapeutics S. Ahmed Consultant or advisory role Tessa Therapeutic's advisory committee Research funding: Seattle Genetics, Merck, Xencor, and Tessa Therapeutics J. R. Westin Consultant or advisory role Research funding: Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Abbvie, SeaGen, MonteRosa, Regeneron Research funding: Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Calithera

PEMBROCABOSARC: Combination of pembrolizumab and cabozantinib in patients with advanced sarcomas.

TPS11586 Background: Despite optimal treatment, up to 40% of patients with sarcomas will develop locoregional and/or distant relapse and median survival in this setting is less than two years. There are very few options in the treatment of undifferentiated pleomorphic sarcomas whereas there is no specific treatment regimen established for recurrent osteosarcoma (OSS) and Ewing sarcoma (ES). Innovative strategies are therefore urgently needed in these settings. In preclinical studies, while immune checkpoint inhibitors were insufficient in controlling tumour growth, combining them with M2 macrophage or angiogenesis targeting resulted in superior tumour control (Mao et al, Clin Cancer Res 2016; Zhu et al, Cancer Res 2014). Combining both antiangiogenic and MET inhibition properties, cabozantinib has shown both preclinical and clinical activity, notably in osteosarcoma and Ewing sarcoma (Italiano et al. ESMO 2018). Interestingly, cabozantinib has also recently been shown to trigger an innate immune response in a preclinical model (Patnaik et al, Cancer Discov 2017). Altogether, these findings pave the way for studies assessing the impact of targeting angiogenesis, MET and immune response in soft-tissue and bone sarcomas. Methods: PEMBROCABOSARC (NCT05182164) is a multi-stratum, three single-arm phase 2, multicenter, open-label study investigating pembrolizumab combined with cabozantinib in patients with advanced selected sarcomas: undifferentiated pleomorphic sarcoma (stratum 1), osteosarcoma (stratum 2), Ewing sarcoma (stratum 3). Strata 1 and 2 will enroll ~32 patients and stratum 3 ~55 patients, respectively. Each stratum phase II will be conducted using a Simon's optimal two-stage design. Eligible and consented patients must be ECOG PS 0–1, have measurable and progressive disease according to RECIST 1.1 and have received less than 3 previous lines of systemic therapy for advanced disease and consent also to baseline and per treatment biopsies. Cabozantinib will be administered orally, once daily at a fixed dose of 40 mg, continuously. Pembrolizumab will be administered by intravenous infusion every 3 weeks on Day 1 of each cycle, at a fixed dose of 200 mg. Both treatments will start on Day 1 (of cycle 1). The primary endpoint is 6-months non progression rate as per RECIST 1.1. Secondary endpoints include adverse events (AEs)/serious AEs, best overall response, and progression-free survival. Pharmacodynamic and other biomarkers will be explored on blood and tumor tissue. The first patient received study drug on May, 31, 2022; 8 of planned 119 patients have been enrolled and 5 sites across France among the planned 10, are currently enrolling patients. Clinical trial information: NCT05182164 .

Dose expansion results of the bifunctional EGFR/TGFβ inhibitor BCA101 with pembrolizumab in patients with recurrent, metastatic head and neck squamous cell carcinoma.

6005 Background: Pembrolizumab (P) is approved to treat patients (pts) with recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). BCA101 is a first-in-class bifunctional EGFR antibody fused to a TGFβ immune modulating payload which is well tolerated and has clinical activity as monotherapy and in combination with pembrolizumab in advanced solid tumors (ESMO 2022 731MO). Here we report the results from the interim analysis of an expansion cohort combining BCA101+P as first line therapy in R/M HNSCC. Methods: This ongoing single-arm, open-label multicenter dose expansion cohort enrolled pts with R/M HNSCC with a tumor PD-L1 CPS≥1 with no prior systemic therapy for R/M disease, ECOG 0-1, and measurable disease (RECIST v1.1). Pts received BCA101 (1500 mg IV on days 1, 8, 15) with P (200 mg IV on day 1) every 21-days. Primary endpoint: safety; secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS). Exploratory: molecular and immunologic predictors of response. A Simon optimal two-stage design was employed: among 18 evaluable pts in stage 1, >3 pts in response triggered continuation to stage 2 enrolling 21 additional pts targeting an ORR>35%. Results: From 2/2022 to 1/2023, 20 pts enrolled while 18 were evaluable (had first restaging scans) in stage 1. Pts were more often men (n=13, 65%) with a median age of 66 (range: 31-77). Oropharynx (10, 50%) [7/10 (70%) were HPV/p16-pos] and oral cavity (7, 35%) were the most common primary subsites (larynx/hypopharynx: 3). Fifteen (75%) had distant metastatic disease. The ORR in stage 1 was 44% (8 PRs, 4 SD) with a clinical benefit rate (CBR=PR+SD) of 67%; 7/12 (58%) HPV-neg pts achieved a response. Median DOR not reached, but median time on-treatment was 6.7 months (range: 2.7-11.0+) among responders. Ten pts discontinued therapy; all but 1 for PD (n=1 for toxicity). Grade 3+ treatment-related adverse events (TRAEs) were observed in 4 pts (20%, most common: anemia). No treatment-related deaths were observed. Acneiform rash was the most common TRAE of any grade (15, 75%). PFS and OS estimates are forthcoming. Eight (44%) had baseline PD-L1 CPS scores of 0-19, while ten (56%) were ≥20. Stage 2 is actively enrolling with completion of accrual expected by the meeting. Conclusions: Stage 1 of this dose expansion cohort of BCA101+P shows encouraging anti-tumor activity with additive potential, particularly among HPV-neg pts; and the combination is well tolerated among this R/M HNSCC population. Further investigation is warranted. Study funded by Bicara Therapeutics and conducted in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. USA (NCT04429542). Clinical trial information: NCT04429542 . [Table: see text]

A phase II trial of pevonedistat plus docetaxel in patients with previously treated advanced non–small-cell lung cancer (NSCLC).

e21062 Background: For patients with stage IV NSCLC, treatment options are limited after progression on immunotherapy (IO) +/- platinum-based chemotherapy. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRLs) catalyze the ubiquitylation and degradation of tumor suppressor proteins and are overactivated in NSCLC. Therefore, inhibition of CRLs has potential therapeutic value. Neddylation is required to activate CRLs; NAE (NEDD8 activating enzyme) catalyzes neddylation. In pre-clinical studies, pevonedistat, a first-in-class small molecule NAE inhibitor, exerts anti-tumor effects when combined with docetaxel. Methods: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with stage IV NSCLC with progression on or after platinum-based chemotherapy +/- IO. Patients with tumors that had driver mutations in EGFR, ALK, ROS1, and BRAF must have also had progression on targeted inhibitors. A Simon Optimal two-stage design was utilized with 90% power and 15% type I error to detect the drug as promising when the true response rate is 25% and the historical control rate is 10%. A maximum of 37 response-evaluable (R-E) patients could be enrolled. Patients received docetaxel 75 mg/m2 on day 1 and pevonedistat 25 mg/m2 on days 1, 3 & 5 of a 21-day cycle. Response was assessed every 2 cycles based on RECIST v1.1 criteria. The primary objective was overall response rate (ORR). Those who received 2 cycles or had progression prior to the end of cycle 2 were considered R-E. Patients who received any treatment on protocol were evaluable for safety (S-E). Results: From 3/5/2018 to 1/26/2021, we enrolled 31 patients and 27 were R-E with a median follow-up of 38.7 months. The trial was terminated early due to the sponsor’s decision to discontinue the development of pevonedistat. In the R-E population, 52% were female with a median age of 63 and 85% had adenocarcinoma. The median number of prior regimens was 2, and 92% of patients had previously received IO. The ORR was 22% (95%CI 8.6-42.3%) and the disease control rate (SD+CR+PR) was 66.7% (95%IC 46.0- 83.5%). The median PFS was 4.1 (2.8-5.8) months and median OS was 13.1 (6.7-24.8) months. The median duration of response was 14.5 months. The incidence of Grade 3-4 adverse events (AE) was 53% in the 30 S-E patients. The most common grade 3-4 AEs were decrease in blood counts (anemia and neutropenia) and elevation in liver transaminases. There were no Grade 5 toxicities. Conclusions: Our data suggest that the combination of docetaxel and pevonedistat is safe and may have improved anti-tumor activity compared to historical data with docetaxel alone. These results suggest that the neddylation pathway is a targetable anti-tumor pathway that should be further studied in patients with NSCLC. Clinical trial information: NCT03228186 .

A phase II study of olaparib (AZD2281) in patients (Pts) with metastatic/advanced urothelial carcinoma and other genitourinary (GU) tumors with DNA-repair defects.

TPS4607 Background: Olaparib is a poly-ADP-ribose polymerase (PARP) inhibitor that induces synthetic lethality in tumor cells with dysfunctional DNA damage repair (DDR) from loss of function of BRCA or other DDR genes. It improves survival in advanced ovarian, pancreatic, prostate and breast carcinoma with DDR gene alterations and is FDA approved for these indications. PARP inhibitors still have an undefined role in non-prostate GU tumors. We hypothesize that PARP inhibitors will have activity in DDR deficient tumors, regardless of histology. We are conducting a phase 2 trial of olaparib in non-prostate GU cancers with DDR gene defects. Methods: Eligible pts must have metastatic/advanced urothelial carcinoma or other non-prostate GU cancers and have measurable disease by RECIST 1.1. Pts in Cohorts 1 and 2 must harbor tumor or liquid pathologic DDR alterations identified by FoundationOne CDx (F1CDx) panel and reviewed by a molecular genetics review panel: Cohort 1 includes BRCA1, BRCA2, ATM, BAP1, MSH2, PALB2, and BRIP1 alterations, and pts with high tumor mutational burden (TMB) (>15 mutations/megabase); Cohort 2 (exploratory cohort) includes ABL1, ATR, ATRX, BARD1, BRD4, CCND1, CHEK1, CHEK2, DOTIL, FANCC, FANCE, FANCG, FANCL, IKBKE, MEN1, MLH1, MSH2, MSH6, MUTYH, NPM1, PMS2, POLD1, POLE, RAD51, SMARCB1, STEK11, and TP53 alterations. Cohort 3 (natural history) will include pts without pathologic alterations in any Cohort 1 or 2 genes. Pts with eligible gene alterations (Cohorts 1 and 2) will be given olaparib 300mg twice daily until progressive disease, unacceptable adverse events, withdrawal of consent or death. They will have circulating tumor cells (CTCs) collected at baseline and every 4 weeks, and CT restaging every 8 weeks. Pts in Cohort 3 will receive standard of care treatment and have baseline CTC collection and be followed for survival. The primary objective is to evaluate the objective response rates (ORR) in Cohorts 1 and 2. Secondary objectives include progression-free survival (PFS), overall survival (OS) and safety. In these cohorts, the trial will have a Simon optimal two-stage design. In Cohort 1, 25 evaluable pts will be required to provide 90% power with alpha = 0.1 to differentiate between a promising ORR of 30% versus an unacceptably low ORR of 10%. In Cohort 2, 35 evaluable pts will be required to provide 90% power with alpha = 0.05 to differentiate between a promising ORR of 30% versus an unacceptably low ORR of 10%. Exploratory objectives include estimating the distribution of DDR alterations in non-prostate GU malignancies, assessing the effectiveness of NGS in detecting DDR alterations in circulating tumor DNA (ctDNA), assessing levels of baseline CTCs and changes in CTC level with olaparib, and correlating with clinical outcomes. This is an ECTCN network clinical trial and is open to enrollment. Clinical trial information: NCT03375307 .

Nanoparticle albumin-bound (nab) paclitaxel in combination with nivolumab as treatment of recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC) that progressed on a PD-1 inhibitor: A single-arm, phase 2 trial.

6023 Background: Drugs bound to albumin selectively target cancer cells with upregulated macropinocytosis, an endocytic nutrient-scavenging process driven by constitutive hyper-activation of the EGFR, RAS, PIK3CA and Syndecan1 signaling pathways that frequently occur in HNSCC. nab-paclitaxel is an active drug in HNSCC and has immunologic effects that can prime an immune response to PD-1 inhibitors, potentially reversing resistance to these agents. These effects include decreased TREGs, increased pro-inflammatory macrophages and differentiation of MDSC to dendritic cells, increased HLA class I expression and antigen presentation, and recruitment of CD8+ CTLs into tumor. Methods: In a single-arm phase 2 trial, patients with RM-HNSCC that progressed on a PD-1 inhibitor received 28-day cycles of nab-paclitaxel (125 mg/m2 IV days 1, 8, and 15) and nivolumab (480 mg IV day 1). Treatment continued until discontinuation criteria were met. The primary endpoint was objective response, assessed with RECIST1.1 by an independent radiologist. The primary hypothesis was that this regimen would result in a higher objective response rate (ORR) than historically reported with standard chemotherapy or cetuximab in similar patients. A Simon optimal two-stage design tested the null hypothesis (H0: ORR≤30%) versus the alternative hypothesis (H1: ORR=50%) at the type I error rate of 5% and power 0.80. In the first stage, 15 patients were to be accrued. If ≥6 responses occurred, 31 additional patients were to be accrued. The null hypothesis will be rejected if ≥19 responses are observed in these 46 patients. We report the results of the primary endpoint for the first stage of the trial. Results: 15 evaluable patients enrolled into the first stage of the trial. Key tumor characteristics and prior treatment history included HPV status (positive: 8; negative: 7), PD-L1 status (CPS 1-19: 7; ≥20: 8), # of lines of prior systemic treatment for RM disease (1-2: 12; ≥3: 3), interval (months) from prior PD-1 inhibitor (<6: 11; ≥6: 4), duration (months) on prior PD-1 inhibitor (median: 6, range: 1-16), and best response to prior PD-1 inhibitor (PR: 4; SD: 6; PD: 5). Tumor response to nab-paclitaxel and nivolumab occurred in 7 of 15 patients (ORR 47%). The best tumor response was PR (7), SD (5) and PD (3). Conclusions: Among patients with RM-HNSCC that progressed on a PD-1 inhibitor, the ORR with nab-paclitaxel and nivolumab was 47% during the first stage of the phase 2 trial. Enrollment to the second stage is ongoing. Clinical trial information: NCT04831320 .

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in combination with pembrolizumab and carboplatin as first-line treatment of recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC): A single-arm, phase 2 trial.

6016 Background: The homologous recombination deficiency (HRD) phenotype is common in HNSCC and is due to mutation and promoter hypermethylation of DNA repair genes ( BRCA1, BRCA2, ATR, ATM, and FANC) and PTEN. In pre-clinical models of HNSCC, HRD sensitizes tumor to PARP inhibition and to additive antitumor activity of PARP inhibition in combination with platinum agents. PARP inhibitors also activate the STING pathway and upregulate PD-L1 expression, resulting in synergistic antitumor activity when given with PD-1 inhibitors. Olaparib is a highly selective PARP inhibitor that has been safely combined with pembrolizumab and carboplatin. Methods: In this single-arm phase 2 trial, patients with RM-HNSCC, no prior therapy for RM disease, and adequate performance status and organ function received up to six 21-day cycles of olaparib (200 mg bid orally days 1-10), pembrolizumab (200 mg IV day 1), and carboplatin (AUC 5 IV day 1), followed by up to twenty-nine 21-day cycles of olaparib (oral 300 mg bid days 1-21) and pembrolizumab (200 mg day 1). Treatment continued until discontinuation criteria were met. The primary endpoint was objective response, assessed by an independent radiologist using iRECIST. The primary hypothesis was that this regimen would result in a higher objective response rate (ORR) than historically reported with 5-FU, pembrolizumab and a platinum agent in similar patients. A Simon optimal two-stage design tested the null hypothesis (H0 : ORR≤36%) versus the alternative hypothesis (H1 : ORR=62%) at a type I error rate of 10% and 90% power. In the first stage, up to 13 patients could be accrued. If ≥6 responses occur, 16 additional patients will be accrued. The null hypothesis will be rejected if ≥14 responses are observed in these 29 patients. At the end of the first stage, an interim analysis was be performed to assess olaparib delivery during cycles 1 and 2 with the goal of 100% delivery in ≥ 80% of patients. We report the results of the primary endpoint and olaparib delivery for the first stage of the trial. Results: Twelve patients enrolled into the first stage of the trial. Key characteristics included median age 62 years (range 59-74), tobacco history (Y-5; N-7), primary site (oropharynx-7; oral cavity-4; larynx-1), HPV status (positive: 6; negative: 6) and PD-L1 status (CPS 0: 1; 1-19: 4; ≥20: 7). Tumor response occurred in 8 patients (ORR 67%). The best tumor response to date was CR (1), PR (7), SD (3) and PD (1). Olaparib delivery during cycles 1 and 2 was 100% for all patients. Conclusions: Among patients with RM-HNSCC, first-line treatment with olaparib, pembrolizumab and carboplatin resulted in an ORR of 67% during the first stage of the trial. Olaparib delivery was 100%. Enrollment into the second stage is ongoing. Clinical trial information: NCT04643379 .

Abstract CT118: A phase I/II trial of a CXCR1/2 inhibitor in combination with anti-PD-1 for circulating tumor DNA (ctDNA) positive & refractoryRAS-mutated microsatellite stable (MSS) colorectal cancer

Abstract Background: Preclinical CRC models reveal KRAS mutations activate the CXCR2 axis promoting an immunosuppressive tumor microenvironment (TME). This occurs via KRAS repression of interferon regulatory factor 2 (IRF2) resulting in upregulation of CXCL3 chemokines, which bind CXCR2 and recruit myeloid-derived suppressor cells (MDSC; Liao et al, Cancer Cell 2019). MDSCs also accelerate metastases by ‘priming’ the premetastatic niche via promoting egress of tumors cells into the circulation, inhibiting killing by immune cells and promoting extravasation into the tissues (Veglia et al. Nature 2021). SX-682 is a novel oral small-molecule inhibitor of CXCR1/2 chemokine receptors involved in MDSC-recruitment to TME. This proof-of-concept study investigates whether a CXCR1/2 antagonist in combination with anti-PD-1 therapy can overcome de novo immunotherapy resistance in MSS RAS mutated mCRC and eradicate micrometastatic disease in ctDNA positive CRC post definitive therapy. Methods: STOPTRAFFIC-1 is a phase I/II, open-label, dose-escalation/dose expansion study of SX-682 plus nivolumab for patients (pts) with RAS mutated MSS mCRC or ctDNA positive CRC. Key eligibility criteria - Arm A: pts with MSS mCRC with progression or intolerance to 2 prior lines of therapy, ECOG 0/1; Arm B: ctDNA positive post completion of definitive therapy (adjuvant chemotherapy for stage III or metastasectomy for stage IV CRC). Pts will receive SX-682 (5 dose levels: 25 mg, 50 mg, 100mg, 200mg, or 400 mg PO twice daily) in an 8-week cycle with intravenous nivolumab (480 mg) on days 1 and 29. Adverse events per CTCAE v5.0. RECIST assessments every 8 weeks. In dose escalation, pts enter a 3-week monotherapy safety run-in of SX-682 followed by 3-week combination with nivolumab for a six-week dose-limiting toxicity (DLT) period. Cohorts 1-4 have been completed without DLT. Enrollment to Cohort 5 is completed with expansion arms to open February 2023. Dose expansion is a Simon's optimal two-stage design for Arm A. Efficacy will be assessed in the first 15 pts with a requirement of 2 responses in order to enroll 14 additional pts (N=29). Pre- and on-treatment tissue biopsies will be collected. Arm B will enroll 15 pts with positive ctDNA post definitive therapy. Pts will be screened with CLIA certified ctDNA test for minimal residual disease (MRD) and if positive, enrolled for treatment for up to 6 months (m). Pts will undergo radiographic evaluation at 3 and 6m and then every 3-6m for at least 3 years. The primary objectives are to determine safety profile, recommended phase 2 dose, clinical activity & 6m ctDNA clearance rate in CRC pts with MRD following 6m of SX-682 + Nivolumab on Arm B. Translational analyses include correlations of clinical outcomes with genomic and immune biomarkers from paired tissue and plasma samples. Clinical trial information: NCT04599140. Citation Format: Benny Johnson, Cara Haymaker, Van K. Morris, Arvind Dasari, Victoria Serpas Higbie, John Paul Shen, Christine Parseghian, Maria Pia Morelli, Ryan Huey, Michael S. Lee, Jason Willis, Kanwal P. Raghav, Ying Yuan, John Zebala, Ronald A. DePinho, Scott Kopetz, Michael Overman. A phase I/II trial of a CXCR1/2 inhibitor in combination with anti-PD-1 for circulating tumor DNA (ctDNA) positive & refractoryRAS-mutated microsatellite stable (MSS) colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT118.

Neoadjuvant nivolumab (N) + ipilimumab (I) in cisplatin-ineligible patients with upper tract urothelial cancer (UTUC).

511 Background: Perioperative platinum-based chemo for UTUC improves pathologic responses and disease-free survival (DFS) while anti-PD1 monotherapy has limited activity to date (PURE-02). Here, we report the results from stage 1 of a phase II neoadjuvant trial of N+I for cisplatin-ineligible patients (pts) with UTUC. Methods: Cisplatin-ineligible pts with histologically confirmed high-grade UTUC and/or radiographically invasive UTUC with positive selective urine cytology were eligible. Pts were treated with I 3mg/kg + N 1mg/kg (weeks [wk] 0, 6), and N 3mg/kg (wk 3) prior to radical nephroureterectomy (NU). The primary endpoint (EP) was pathologic complete response (pCR, ypT0pN0) and secondary EPs included <ypT2pN0 rate, DFS, and toxicity. The study has a Simon optimal two-stage design: if ≥1/9 pts achieved pCR in stage 1, the trial would proceed to accrue 24 total pts. Next generation sequencing of pre-treatment tumors was correlated with pathologic response. Results: Nine pts were enrolled between 2/2021-7/2022 with median age 71 (range 62-86), 89% male. Primary sites included ureter, n=6; renal pelvis, n=2; and both, n=1. Four pts (44%) had hydronephrosis. Median tumor diameter was 3.0 cm, (range: not measurable to 4.2 cm). Six pts (67%) received all planned treatment; N+/-I was stopped early for CTCAE grade 2 hyperthryoidism, n = 1; grade 2 diarrhea, n = 1; and grade 3 pneumonitis, n = 1. Median time from last treatment to NU was 1.7 months (range 0.6-3.7). No progression was noted on systemic therapy and all pts underwent NU, with pCR in 3/9 pts (33%) and <ypT2pN0 in 6/9 (67%). Two pts had metastatic recurrence at 10.3 and 15.6 months after treatment initiation, while 1 pt died of post-op complications related to bowel leak 7.2 months after N+I initiation (4.7 months after NU) and 1 died 9.2 months after N+I initiation (4.7 months after NU) from complications of a fall unrelated to disease, surgery or N+I. Median tumor mutational burden (TMB) in 7 pts with pre-treatment sequencing was 13.2 mutations/megabase (range 6.6-106.3); all 3 pts with TMB<10 were >ypT1 or node positive at NU and all 4 pts with TMB>10 were <ypT1pN0. Three pts (43%) had FGFR3 driver mutations. Three pts had confirmed pathogenic germline variants in mismatch repair genes (MSH2, n=2; MLH1, n=1), all of which achieved pCR (n=1) or ypTaN0 (n=2) and remained alive and disease-free at last follow-up. CTCAE grade ≥3 treatment-related adverse events occurred in 4 pts (1 myasthenia, 1 maculopapular rash, 1 pneumonitis, 1 hepatitis plus elevated lipase). Conclusions: In this cohort of cisplatin-ineligible pts with UTUC, neoadjuvant N+I showed clinical activity meeting the trial’s Simon optimal two-stage design’s criteria to proceed to the second stage. All pts with pathogenic germline variants in mismatch repair genes achieved <ypT1pN0 and remain free of disease. Clinical trial information: NCT03520491 Clinical trial information: NCT03520491 .

50 (PB040) - A phase 1/2, open-label, multicenter study to investigate the safety, pharmacokinetics, and efficacy of fadraciclib (CYC065), an oral CDK2/9 inhibitor, in subjects with advanced solid tumors and lymphoma

Background: Fadraciclib is a highly selective, orally- and intravenously-available, 2nd generation amino-purine inhibitor of CDK2 and CDK9. Translational biology supports the development of fadraciclib as a therapeutic agent for cancers dependent on MCL1 and MYC through the inhibition of CDK9, and for cancers associated with CCNE1 amplification, a known resistance factor for trastuzumab and CDK4/6 inhibitors, through the inhibition of CDK2. By inhibiting CDK2 and 9, fadraciclib causes apoptotic death of cancer cells at sub-micromolar concentrations. In an earlier Phase 1 study of IV fadraciclib, confirmed CR has been achieved in a subject with MCL1-amplified endometrial cancer. Oral fadraciclib is highly bioavailable allowing flexibility of dosing and schedule. Methods: Fadraciclib is being evaluated in a global, open-label, non-randomized, dose-escalation (phase 1) study in subjects with advanced solid tumors or lymphoma, and proof of concept (phase 2) in subjects with targeted indications, designated CYC065-101, (NCT04983810). Phase 1 explores both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify MTD and/or RP2D. Once RP2D is established, phase 2 will enroll 12 to 40 subjects in seven specific tumor-type groups and a basket cohort, utilizing a Simon two-stage optimal design to evaluate clinical activity. Phase 2 groups include endometrial or ovarian cancer, biliary tract cancer, hepatocellular carcinoma, breast cancer, B-cell lymphoma, T-cell lymphoma, metastatic colorectal cancer and a basket cohort for tumors with MCL1, MYC or CCNE amplification/overexpression. Results: CYC065-101 study started enrolling subjects in July 2021 and is ongoing at City of Hope National Cancer Center, MD Anderson Cancer Center, Seoul National University Hospital, and Vall d’Hebron Institute of Oncology. As of June 2022, 17 subjects have received fadraciclib at dose levels 1 to 5. Fadraciclib was well tolerated at all dose levels with no DLT and no SUSAR observed. Preliminary efficacy data are available for 16 patients. One patient with CTCL showed PR per mSWAT response criteria. At dose level 5, a patient with endometrial cancer showed 15% reduction of target lesions after first cycle of treatment, and a patient with Angioimmunoblastic T-Cell Lymphoma (AITL) showed extensive reduction in multiple lesions after first cycle of treatment. PK, PD, and PGx including NGS and RNA-Seq are being evaluated in phase 1 subjects. Preliminary PK analysis suggests dose dependent exposure. Studies on MYC, MCL1, and PPP1R10 mRNA in peripheral blood samples after fadraciclib treatment will be shown. Conclusion: Based on data from the CYC065-101 study, fadraciclib appears to be well tolerated from dose levels 1 to 5. No drug related SAEs, SUSAR or DLTs were reported. The trial is ongoing with a primary endpoint of defining MTD and RP2D. Conflict of interest: Advisory Board: D. Oh: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA M. Villanona-Calero: Eli Lilly Corporate-sponsored Research: S. Piha-Paul: AbbVie, ABM Therapeutics, Acepodia, Alkermes Aminex Therapeutics Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim Bristol Myers Squib Cerulean Pharma, Chugai Pharmaceutical, Curis, Cyclacel Pharmaceuticals Daiichi Sankyo Eli Lilly ENB Therapeutics Five Prime Therapeutics F-Star Beta Limited F-Star Therapeutics Gene Quantum Genmab A/S Gilead Sciences, GlaxoSmithKline Helix BioPharma, HiberCell, Immunomedics, Incyte, Jacobio Pharmaceuticals, Lytix Biopharma AS Medimmune, Medivation, Merck Sharp and Dohme, Novartis Pharmaceuticals Pieris Pharmaceuticals, Pfizer Phanes Therapeutics Principia Biopharma, Puma Biotechnology, Purinomia Biotech, Rapt Therapeutics, Seattle Genetics Silverback Therapeutics Synlogic Therapeutics Taiho Oncology Tesaro, TransThera Bio ZielBio, NCI/NIH, P30CA016672 – Core Grant (CCSG Shared Resources) Consulting: CRC Oncology D. Oh: Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok E. Garralda: Research: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/ BeiGene Consultant/Advisor: Roche/Genentech - F.Hoffmann/La Roche/ Ellipses Pharma/Neomed Therapeutics1 Inc/Boehringer Ingelheim/Janssen Global Services/SeaGen/Alkermes/Thermo Fisher/Bristol-Mayers Squibb/ MabDiscovery/Anaveon/F-Star Therapeutics/Hengrui Speakers Bureau: Merck Sharp & Dohme/Roche/Thermo Fisher/Lilly/Novartis Clinical Trials PI or Co-PI (Institution): Affimed Gmbh - Amgen SA – Anaveon AG – AstraZeneca AB – Biontech Gmbh – Catalym Gmbh - Cytomx - F.Hoffmann La Roche Ltd – F-Star Beta Limited - Genentech Inc - Genmab B.V. – Hutchison Medipharma Limited – Icon - Imcheck Therapeutics – Immunocore Ltd – Janssen-Cilag SA – Medimmune Llc – Merck Kgga – Novartis Farmacéutica, S.A – Peptomyc – Ribon Therapeutics – Roche Farma SA – Seattle Genetics Inc – Symphogen A/S – Taiho Pharma Usa Inc M. Vieito: Travel grants: Roche, EMD/Serono Consulting: Roche, Debiopharm M. Villanona-Calero: Speakers Bureau: Amgen Other Substantive Relationships: J. Huang: Employee of Cyclacel, the trial sponsor M. Kirschbaum: Employee of Cyclacel, the trial sponsor M. Villanona-Calero: Stocks: Moderna

STOPTRAFFIC-1: A phase I/II trial of SX-682 in combination with nivolumab for refractory RAS-mutated microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

TPS3638 Background: Refractory RAS mutated MSS mCRC represents a critical unmet need with minimal response to immune checkpoint blockade (ICB). Preclinical CRC models reveal that KRAS mutations activate the CXCR2 axis promoting an immunosuppressive tumor microenvironment (TME). This occurs via KRAS repression of interferon regulatory factor 2 (IRF2) resulting in upregulation of CXCL3 chemokines, which bind CXCR2 and recruit myeloid-derived suppressor cells (MDSC; Liao et al, Cancer Cell 2019; Grover et al, Cancer Discovery, 2022). SX-682 is a novel oral small-molecule inhibitor of the CXCR1/2 chemokine receptors involved in MDSC-recruitment to the TME. This proof-of-concept study investigates whether de novo immunotherapy resistance in MSS RAS mutated mCRC can be overcome by treatment with a small molecule CXCR1/2 antagonist in combination with anti-PD-1 therapy. Methods: STOPTRAFFIC-1 (NCT04599140, enrolling) is a phase I/II, open-label, dose-escalation/dose expansion study of SX-682 in combination with nivolumab to evaluate safety and clinical activity for patients (pts) with refractory RAS ( KRAS and NRAS) mutated MSS mCRC. Key eligibility criteria: patients (pts) with MSS mCRC with measurable disease, progression or intolerance to at least 2 prior lines of standard therapy, and ECOG 0 or 1. Pts will receive SX-682 (5 dose levels: 25 mg, 50 mg, 100mg, 200mg, or 400 mg by mouth twice daily) administered in an 8-week cycle with intravenous nivolumab (480 mg) on days 1 and 29 of each cycle. Adverse events are assessed according to CTCAE v5.0. Response assessments (per RECIST) occur every 8 weeks. In dose escalation, pts enter a 3-week monotherapy safety run-in of SX-682 followed by 3-week combination with nivolumab for a six-week dose-limiting toxicity (DLT) period. Cohorts 1-4 have been completed without DLT. Enrollment to cohort 5 began in January 2022. Following determination of maximum tolerated dose (MTD), dose expansion design is a Simon's optimal two-stage design. Efficacy will be assessed in the first 15 pts with a requirement of at least 2 responses in order to enroll 14 additional pts (N=29) in the second stage. Pre- and on-treatment tissue biopsies will be collected in the expansion phase. The primary objectives are to determine the safety profile of SX-682 alone and in combination with nivolumab, including the MTD, recommended phase 2 dose, and the DLT. The secondary objectives include overall response rate, progression-free survival, overall survival, and pharmacokinetic profiles of SX-682. Translational analyses include correlations of clinical outcomes with genomic and immune biomarkers from paired tissue and plasma samples. Clinical trial information: NCT04599140.

Results of a phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response pathway deficient neoplasms.

3122 Background: BRCA1-Associated Protein 1 (BAP1) acts as a tumor suppressor and critical regulator of the cell cycle and DNA damage response (DDR). PARP inhibitors (PARPi) demonstrate synthetic lethality in BAP1 mutant (mBAP1) preclinical models, independent of underlying germline BRCA status. mBAP1 leads to a loss of functional protein in several solid tumors. This study aimed to explore the clinical activity of niraparib in patients (pts) with advanced tumors likely to harbor mBAP1. Methods: Eligible adult pts with measurable metastatic solid tumors having exhausted approved therapies, adequate organ function, and ECOG PS 0-1 were assigned to Cohort A (histology-specific): tumors likely to harbor mBAP1 (i.e., cholangiocarcinoma, uveal melanoma, mesothelioma, or clear cell renal cell carcinoma) with tissue available for mBAP1 confirmation; or Cohort B (histology-agnostic): tumors with other known non-BRCA confirmed DDR mutations. Known BRCA1 or 2 mutations or prior PARPi exposure were excluded. All pts received niraparib 200-300mg daily, depending on weight and/or platelet count. Radiographic response was assessed by RECIST v1.1 measured every 8 weeks while on treatment. The primary endpoint was ORR with secondary endpoints of PFS, OS, clinical benefit (CR+PR+SD), toxicity, and exploratory biomarker determinations. Cohort A employed Simon's optimal two-stage design to assess a 30% ORR increase (a = 0.05; power = 90%). Cohort B aimed to assess a 40% ORR increase for this molecularly selected/enriched patient population. Results: From 08/13/2018 to 12/21/2021, 37 pts enrolled from two different centers, with 32 evaluable for response (Cohort A n = 18; Cohort B n = 14). In Cohort A, best ORR was 1 PR (6%), 8 SD (44%; median 5.7 mo; range 2 - 9.4 mo), and 9 PD (50%). Cohort A was stopped at the first stage following the pre-specified Simon’s design. mBAP1 was confirmed in 7/9 pts (78%) with PR or SD but in only 2/9 (22%) in those with PD. In Cohort B, best ORR was 6 SD (43%; median 7.5 mo; range 3.3 - 8.6 mo) and 8 PD (57%). Mutations in those with SD included ATM, CHEK2, PTEN, RAD50, and ARID1A. Common grade 3/4 AEs observed were anemia (16%), thrombocytopenia (16%), nausea (11%), and vomiting (8%). There were no unexpected nor grade 5 toxicities. Conclusions: The use of niraparib was well tolerated in pts with advanced treatment refractory solid tumors but failed to meet pre-specified efficacy threshold of ORR. However, clinical benefit was identified in 78% of patients in cohort A who had a confirmed mBAP1 tumor. Further correlative analyses are ongoing and additional clinical development restricted to mBAP1 tumors may be justified. Clinical trial information: NCT03207347.