Experimental Therapeutics Clinical Trials Network Research Articles

Abstract CT159: Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495)

Abstract Background: Human epidermal growth factor receptor 2 (HER2) overexpression, amplification, or mutation occurs across a variety of solid tumors. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has been approved by the FDA for HER2-overexpressed advanced breast, gastroesophageal cancers, HER2-low breast cancer, and HER2-mutated non-small cell lung cancer. However, some patients do not derive clinical benefit from T-DXd, and drug resistance is inevitable. Preclinical studies demonstrated that neratinib, an oral irreversible pan-HER tyrosine kinase inhibitor, can increase uptake of HER2-targeting ADCs, including ado-trastuzumab emtansine and T-DXd, in vivo. Enhanced uptake of ADC is postulated to be secondary to hindering HSP90 binding to the HER2 receptor, thereby inducing receptor ubiquitination and internalization. This finding was further confirmed in patient-derived xenograft models from two patients with HER2-mutated, but non-amplified, low-expressing advanced breast cancer. Therefore, we hypothesized that the combination of T-DXd and neratinib in patients with advanced solid tumors with a HER2 alteration will enhance the efficacy of T-DXd. As T-DXd and neratinib may have overlapping toxicities in patients, a phase I study to establish the safety of the combination is warranted. Methods: This is a multi-center, phase I clinical trial (NCT05372614, NCI 10495) with a 3+3 design to study the safety and tolerability of T-DXd and neratinib. The trial is supported by the National Cancer Institute Experimental Therapeutics Clinical Trials Network. Eligible patients have advanced solid tumors with HER2 overexpression, amplification by ISH/NGS, or an activating HER2 mutation. Up to 18 evaluable patients will be enrolled in the dose escalation portion (Part 1), and 12 patients will be enrolled in the pharmacodynamic cohort (Part 2). During Part 1, the maximum tolerated dose and recommended phase 2 dose will be determined for neratinib. The dose of T-DXd is fixed at 5.4 mg/kg. We are actively enrolling patients in Part 1. The primary endpoint is dose-limiting toxicities of the combination during the first 2 cycles of treatment (42 days). Key secondary objectives of the study include T-DXd payload (DXd/MAAA-1181a) in tumor tissue obtained before and after co-treatment with neratinib to assess the potential enhanced payload concentration with the combination and quantitative HER2 assessed by mass spectrometry using multiplex reaction monitoring. Citation Format: Andrew A. Davis, Ecaterina E. Dumbrava, Aparna Kalyan, Nataliya V. Uboha, Haider S. Mahdi, Reema A. Patel, Farshid Dayyani, Jessica Porzel, Whitney L. Hensing, Cynthia X. Ma, Ron Bose, Haeseong Park. Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT159.

Abstract IA029: Expanding access and participation to early phase clinical trials for our underrepresented populations

Abstract The American Society of Clinical Oncology (ASCO) has a firm position that phase I trials provide trials participants potential benefit with improved quality of life, psychological and direct medical benefit. Disproportionate access to novel therapies through early phase clinical trials among underrepresented populations continues to exist. In fact, there is worsening disparity in accrual of patients from racial and ethnic minority groups in phase 1 trials of drugs for metastatic cancer. Access to cutting-edge clinical trials leading to paradigm-changing treatments is critical for cancer care and equity in society, as participation in clinical trials correlates with reduction in mortality. Stark disparities in access and participation to clinical trials impact underserved populations among racial and ethnic minorities, socioeconomically disadvantaged, and geographically isolated populations. The impact of newer therapies, if inadequately studied in underserved populations, may result in poor generalizability of study results and uncertain benefit for these groups. Further, evidence suggests that access to clinical trials narrows the gap in cancer care disparity among patients in urban and rural communities. In response to ethical, clinical, and biologic mandate, the National Cancer Institute’s (NCI) Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) was created. This congressional mandate was a P30 administrative supplement awarded to eight NCI-designated cancer centers to enhance access to early phase precision medicine Experimental Therapeutics Clinical Trials Network (ETCTN) clinical trials for minority and underserved populations. The purpose of this presentation is to share best practices learned in CATCH-UP.2020 and discuss how this program helped create a roadmap to building a clinical trials ecosystem that allowed expanded access to early phase trials through cross-fertilization of successful tools among the CATCH-UP sites and within ETCTN. In our institution, learned best practices are applied across the spectrum of early phase clinical investigations to help overcome clinical trials disparities using the rural lens. With the goal of bringing precision medicine clinical trials close to home for our underrepresented populations, we aim to accelerate drug development without leaving anyone behind. Citation Format: Joaquina C. Baranda. Expanding access and participation to early phase clinical trials for our underrepresented populations [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr IA029.

Expanding eligibility criteria for renal and liver function in NCI-sponsored immunotherapy clinical trials.

e13610 Background: Stringent eligibility criteria can slow accrual, impede evaluation of potentially promising anticancer therapies, and limit applicability of trial results to the larger population. Immuno-Oncology (IO) clinical trials utilizing anti-PD1/PDL1 monoclonal antibodies (mAb) are ideal candidates to broaden organ function (fcn) eligibility, as their kinetics are independent of renal or hepatic fcn. Herein we present an analysis of the current landscape of renal and hepatic eligibility criteria in NCI CTEP-sponsored IO clinical trials to determine if these meet the recommended guidelines for broadened criteria. Methods: We conducted a retrospective analysis of renal and hepatic fcn eligibility criteria of NCI-sponsored IO trials in the CTEP networks initiated by the data cut-off date of 4/24/22. At least one treatment arm on all included trials had an anti-PD1/PDL1 mAb either alone or in combination with other agents. ASCO and Friends of Cancer Research (ASCO/Friends) recommendations and the NCI broadened eligibility criteria were used to assess the trials. ASCO/Friends broadens inclusion criteria for renal fcn to a creatinine clearance (CrCl) of > 30 mL/min but gives no specific hepatic fcn cutoff. NCI recommends broadened criteria to glomerular filtration rate (GFR) of ≥ 60 mL/min/1.73m2 for the Experimental Therapeutics Clinical Trials Network and all phase 1 trials or GFR ≥ 50 mL/min/1.73m2 for National Clinical Trials Network (NCTN) trials, unless safety data exists for lower renal fcn values, and no lower than 30 mL/min/1.73m2. NCI suggests hepatic fcn criteria with total bilirubin ≤ institutional upper limit of normal (ULN) and AST/ALT ≤ 3 × ULN. CrCl and GFR were deemed interchangeable in this analysis. Results: A total of 182 IO trials were identified. Of these, 45 (25%) required CrCl > 30 mL/min. Three trials (2%) allowed for CrCl < 30 mL/min: one trial each requiring CrCl > 25 mL/min, 20 mL/min, and 15 mL/min. One trial had no renal criteria. Ninety-five trials (52%) were compliant with the suggested NCI template guidance but not ASCO/Friends: 20 trials with CrCl > 60 mL/min, 48 trials with > 50 mL/min, 10 trials with > 45 mL/min, and 17 trials with > 40 mL/min as the renal eligibility criteria. Thirteen trials (7%) did not abide by either guidance: 6 NCTN trials with CrCl > 60 mL/min and 4 trials requiring CrCl > 70 mL/min. Serum creatinine alone was utilized for renal fcn in 22 trials. For hepatic criteria, 82 trials (45%) complied with NCI recommendations. The other 100 trials (55%) did not utilize the suggested NCI template cutoff for AST/ALT of 3 x ULN, but 81 of these trials allowed for AST/ALT at 2.5 x ULN with 27 of the 81 trials allowing for 5 x ULN for AST/ALT if liver metastases were present. Conclusions: Our results demonstrate that clinical trials have updated toward broadening hepatic eligibility criteria but require further guidance to facilitate a less cautious approach with renal fcn.

ETCTN 10450: A phase I trial of peposertib and lutetium 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

TPS658 Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium 177 DOTATATE (Lutathera) is a beta-emitting radionuclide, FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 17% ORR. Peptide receptor radionuclide therapy (PRRT) also doesn’t seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Radiation is a potent inducer of DNA double-strand break (DSB); targeting signaling networks involved in DSB repair is a promising approach for enhancing cellular radiosensitivity. The primary repair mechanism of radiation-induced DSBs is nonhomologous end-joining (NHEJ) pathway, in which the DNA-PK (Deoxyribonucleic acid protein kinase) complex plays a pivotal role. Upregulation of DNA-PK promotes repair of DSBs leading to tumor radio-resistance preclinically and clinically. Thus, DNA-PK is an important molecular target for inhibiting DSB repair and enhancing the cytotoxicity of radiation. Peposertib is a selective inhibitor of DNA-PK that targets tumor cell DNA damage repair and survival by blocking NHEJ. We previously reported strong anti-tumor activity when Peposertib was used as radiation sensitizer in pre-clinical NET models. Methods: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of peposertib and Lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation with help of Bayesian optimal interval design (BOIN) and dose expansion cohorts. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Patients will be treated with 177 lutetium dotatate in combination with peposertib. Peposertib will be administered orally from D1-21 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate recommended phase II dose (RP2D). Secondary endpoints are to evaluate safety, pharmacokinetics, and clinical activity (ORR and PFS). We are also evaluating Lu-177 DOTATATE dosimetry in collaboration with NIH IROC and plasma hPG80, a novel blood based diagnostic biomarker. In addition, the study will correlate clinical outcome with somatic tumor mutations and germline mutations. Clinical trial information: 04750954 .

ETCTN 10476: A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without addition of cobimetinib in previously treated unresectable biliary tract cancer.

TPS639 Background: The combination of the MEK inhibitor, Cobimetinib, with the PD-L1 antagonist, Atezolizumab, significantly improved progression-free survival (PFS) compared to Atezolizumab monotherapy in patients with advanced biliary tract cancer (BTC) following first-line chemotherapy (NCT03201458). Interrogation of biospecimens from this trial and parallel pre-clinical work showed that the addition of MEK inhibition enhanced tumor immunogenicity but simultaneously had detrimental effects on host T-cell activation and priming. The addition of immune co-stimulants rescues T-cell function in the setting of systemic MEK inhibition in vivo. Unlike other immune co-stimulatory markers, CD27 is one of the most positively differentially expressed receptors in the TME post-treatment with combined MEK inhibition and PD-L1 blockade. We hypothesize that addition of CD27 immune agonism to the combination of PD-L1 and MEK inhibition can improve immunotherapy outcomes in patients with BTC. Methods: We are conducting an open-label, randomized ph 2 trial evaluating a PD-L1 inhibitor (atezolizumab) in combination with a CD27 immune agonist (CDX-1127 [Varlilumab]) with or without addition of a MEK inhibitor (Cobimetinib) in patients with unresectable, previously treated, BTC. Key inclusion criteria include: adults with pathologically-confirmed BTC, s/p 1-2 lines of systemic therapy (including any FDA-approved targeted therapies) in the metastatic setting, measurable disease, ECOG performance status ≤1, adequate baseline organ and marrow function. Patients who have received gem-cis-durvalumab, and/or prior FGFR2/IDH1 targeted therapy are eligible for enrollment. The study is planned for 64 evaluable subjects (32 subjects per treatment arm) randomized in a 1:1 ratio, stratified by site of BTC location, to either Atezolizumab + CDX-1127 or Atezolizumab + CDX-1127 + Cobimetinib. During the 28-day treatment cycles, all patients receive Atezolizumab (840mg flat dose) and CDX-1127 (3mg/kg) infusions on D1 and D15. For those randomized to the triplet regimen arm, the additional Cobimetinib will be dosed orally at 60mg daily on days 1-21. Overall response rate and PFS are co-primary endpoints. A clinically meaningful improvement in ORR warranting further study is 20%. The primary correlative outcome is treatment-related changes in CD8+ infiltrating T cells. After an initial safety lead-in, a planned interim efficacy analysis will take place following enrollment of the first 18 patients in each treatment arm. Currently, 14 participants (n=6 [triplet arm], n=8 [doublet arm]), have been enrolled & treated on protocol. This study is sponsored by the NCI Cancer Therapy Evaluation Program and is open nationally at designated NCI Experimental Therapeutics Clinical Trials Network sites. Clinical trial information: NCT04941287 .

Expanding access to early phase trials: the CATCH-UP.2020 experience.

Disparities in cancer outcomes persist for underserved populations; one important aspect of this is limited access to promising early phase clinical trials. To address this, the National Cancer Institute-funded Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) was created. We report the tools developed and accrual metrics of the initial year of CATCH-UP.2020 with a focus on racial, ethnic, geographic, and socioeconomically underserved populations. CATCH-UP.2020 is a P30 supplement awarded to 8 National Cancer Institute-designated cancer centers with existing resources to rapidly open and accrue to Experimental Therapeutics Clinical Trials Network (ETCTN) trials with emphasis on engaging patients from underserved populations. Sites used patient-based, community-based, investigator-based, and program-based tools to meet specific program goals. From September 2020 to August 2021, CATCH-UP.2020 sites opened 45 ETCTN trials. Weighted average trial activation time for the 7 sites reporting this was 107 days. In the initial year, sites enrolled 145 patients in CATCH-UP.2020 with 68 (46.9%) representing racial, ethnic, rural, and socioeconomically underserved populations using the broader definition of underserved encompassed in the grant charge. During the initial year of CATCH-UP.2020, a time impacted by the COVID-19 pandemic, 15.8% (66 of 417) and 21.4% (31 of 145) of patients enrolled to ETCTN trials at network and at CATCH-UP sites, respectively, were from racial and ethnic minority groups, a more limited definition of underserved for which comparable data are available. Targeted funding accelerated activation and accrual of early phase trials and expanded access to this therapeutic option for underserved populations.

Expanding the role of advanced practice providers (APPs) in cancer clinical trials.

60 Background: Advanced Practice Providers (APPs) represent a growing and increasingly important component of the oncology workforce. However, APP roles in clinical research are not clearly understood, and certain policies may limit participation. For instance, National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) historically prohibited APPs from signing orders on CTEP-sponsored studies, even at centers where APPs have antineoplastic privileges allowing them to order cancer treatments as standard therapy or on non-CTEP studies. At the UT Southwestern Harold C. Simmons Comprehensive Cancer Center (SCCC), more than 100 active CTEP-sponsored trials account for approximately 30% of therapeutic enrollment. Given these considerations, we approached CTEP regarding potential policy change. Methods: In early 2020, we raised the issue of disparities in allowed APP delegation between (1) CTEP trials and (2) standard practice and non-CTEP trials to NCI/CTEP leadership. Later that year, CTEP organized a discussion on the topic with SCCC representatives and other stakeholders. Subsequently, NCI deployed a survey to National Clinical Trials Network (NCTN) and Experimental Therapeutics Clinical Trials Network (ETCTN) centers asking about the role of APPs at their respective institutions. Results: Following the survey, CTEP revised its policy, allowing appropriately credentialed APPs to sign treatment orders on CTEP-sponsored trials, effective September 1, 2021. After completing required regulatory steps to update trial protocols at UTSW SCCC, approved APPs began signing cancer clinical trial treatment orders in January 2022. Since that time, the proportion of trial treatment orders signed by APPs at SCCC has increased from 1% in January 2022 to 20% in May 2022. Conclusions: The role of APPs in cancer care can be further enhanced by alleviating barriers and allowing providers to perform at the full scope of practice, thereby further integrating care teams critical to compliant and safe clinical trial participation.

Abstract CT170: A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ)

Abstract Background: Ramucirumab is a monoclonal antibody that binds to the vascular endothelial growth factor receptor 2, increasing hypoxia in the tumor microenvironment. In advanced gastric cancer, single agent ramucirumab is well tolerated and improves overall survival (OS) compared to placebo although it is largely cytostatic with a response rate ≤3%. Preclinical in vitro and in vivo experiments reveal that hypoxia induces homologous recombination deficiency (HRD) in tumors, which may be exploited by the addition of inhibitors of poly (ADP-ribose) polymerase (PARPi). We thus designed NCI10066 for metastatic gastric cancer with the hypothesis that ramucirumab would sensitize tumors to the PARPi olaparib. Methods: NCI 10066 (NCT03008278) was a phase 1/2, multicenter, open-label clinical trial sponsored by the Cancer Therapy Evaluation Program. Eligible patients had histologically confirmed metastatic gastric or GEJ adenocarcinoma with measurable disease refractory to ≥ 1 prior therapy that did not contain ramucirumab. Patients were treated with escalating doses of olaparib with ramucirumab 8 mg/kg every 2 weeks in a 3+3 design. Dose escalation evaluated two dose levels: olaparib 200 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 1) and olaparib 300 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 2). The primary objective of dose escalation was to assess safety and measure dose limiting toxicities (DLT) to determine the recommended phase 2 dose (RP2D). The primary objective in phase 2 was to evaluate clinical activity at the RP2D in a 40-patient expansion cohort. Results: From 2/8/18 - 9/17/21, 51 patients were enrolled at 10 centers throughout the Experimental Therapeutics Clinical Trials Network and 28/51 (55%) patients had ≥2 prior lines of therapy. In dose escalation 3 patients were treated at dose level 1 and 8 at dose level 2. No DLTs were observed at dose level 1 and at dose level 2 there was 1 DLT (fatigue) in 6 evaluable patients. The RP2D was determined to be olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. Forty patients were treated in dose expansion at the RP2D. Of 46 patients evaluable for a response there were 5/46 (11%) partial responses (PR) and the disease control rate (PR/SD) was 29/46 (63%) at 6 weeks. The median progression free survival (PFS) was 2.8 months (95% CI 2.3 - 4.2) and the median OS was 7.3 months (95% CI 5.6 - 13.0). Grade ≥ 3 treatment related adverse events were seen in 13 (25%) of patients and there were no treatment related deaths. Conclusions: The combination of olaparib and ramucirumab is well tolerated with a RP2D of olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. The ORR, PFS, and OS exceed the historical control with ramucirumab monotherapy, suggesting that the combination is clinically active. Biomarkers are critical to defining patient subsets more likely to benefit from the combination and HRD biomarker analysis is ongoing. Citation Format: Michael Cecchini, Joseph Chao, Yu Shyr, James Cleary, Nataliya Uboha, May Cho, Anthony Shields, Shubham Pant, Laura Goff, Kristin Spencer, Edward Kim, Chih-Yuan Hsu, Stacey Stein, Jaykumar Thumar, Jeremy Kortmansky, John Kunstman, Patricia LoRusso, Percy Ivy, Jill Lacy. A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT170.

Bringing experimental therapeutics clinical trials network (ETCTN) to underrepresented population.

6542 Background: Access to health care including clinical trials (CT) leading to paradigm-changing cancer treatments are critical for high quality cancer care and equity in society. In this report, we highlight methods in accruing to ETCTN wherein underrepresented rural, low-income, and racial minorities comprise >50% of enrollment. Methods: University of Kansas Cancer Center (KUCC) is one of eight National Cancer Institute (NCI) designated cancer centers awarded CATCH-UP.2020 (CATCH-UP), a congressionally mandated P30 supplement to enhance access for minority/underserved populations to ETCTN precision medicine CT. KUCC catchment area is 23% rural by Rural Urban Continuum Codes (RUCC); almost 90 % of counties are designated primary care HPSA’s (Health Professional Shortage Areas). KUCC Early Phase and Masonic Cancer Alliance (rural outreach network) partnered to operationalize CATCH-UP. We engaged disease-focused champion investigators in disease working groups and MCA physicians who selected scientifically sound CT that fit catchment area needs. Patient and Investigator Voices Organizing Together, a patient research advocacy group provided practical feedback. MCA navigator coordinated recruitment. Telehealth was used for rural patients that would have a significant distance to travel just to be screened. Results: CATCH-UP was initiated in September 2020. Twenty-eight CT were activated, many in community sites. Average activation time was 81 days. Delays were mainly from CT amendments. KUCC enrolled the first patient in the CATCH-UP program. In 6 months, we met accrual requirements (24/year, 50% minorities). During first year, we enrolled 47 (>50% minorities), an increase of 680% from our average accrual of 6/year (>50% minorities) in ETCTN through Early Drug Development Opportunity Program (2016-2020). To date, we have enrolled 61, 54% from rural, HPSA, race and other minorities. Although the proportion of minorities did not change but remained high, this funding allowed us to substantially increase the number of patients from a catchment area with high proportion of geographically and socioeconomically underserved minorities given access to early phase CT through ETCTN. Conclusions: Amid COVID-19 pandemic, the NCI CATCH-UP program and methods we used allowed access to novel therapies for rural, medically underserved, and other minority groups. Funded by NIH: 3P30CA168524-09S2.

Abstract IACC0601: Radiopharmaceuticals and their future in cancer care

Abstract Radiopharmaceutical agents have been an appealing treatment approach since the use of 131I to treat thyroid malignancies. Advances in cancer radiobiology and radiochemistry have brought radiopharmaceuticals forward to the cutting edge of oncology clinical research. The National Cancer Institute (NCI) and its partnering academic and clinical research networks monitor radiopharmaceutical discoveries that might be incorporated into cancer treatment strategies for patients with unmet therapeutic needs. Such endeavors happen through leveraged partnerships between NCI's Cancer Therapy Evaluation Program (CTEP), its Radiation Research Program (RRP), and academic institutions in the Experimental Therapeutics Clinical Trials Network (ETCTN). If innovative discoveries are made, NCI supports clinician scientists to plan new and original radiopharmaceutical phase I and II monotherapy or combination trials. The clinical trial infrastructure needs, such as radiopharmaceutical dosimetry and treatment planning, are now available in government workflow and regulatory oversight. This presentation introduces a modern approach to the clinical development of radiopharmaceutical agents in an era of molecular targets and personalized cancer therapeutics. Citation Format: Charles A. Kunos. Radiopharmaceuticals and their future in cancer care [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr IACC0601.

Abstract CT115: Phase I trial of the triplet berzosertib (M6620, VX-970), veliparib and cisplatin (BVP) in patients with advanced solid tumors

Abstract Background: Ataxia-telangiectasia-related (ATR) protein kinase is central to the repair of damaged DNA through the homologous recombination (HR) pathway. We conducted a phase I trial of cisplatin in combination with the ataxia-telangiectasia-related (ATR) protein kinase inhibitor berzosertib (M6620) and the poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor veliparib, postulating that simultaneous PARP and ATR inhibition impairs DNA repair and induces a “BRCA null”-like phenotype which could potentiate the antitumor activity of cisplatin. We evaluated the safety, maximal tolerated dose (MTD) and preliminary anti-tumor activity of this treatment triplet. The study was conducted through the Experimental Therapeutics Clinical Trials Network (ETCTN). Methods: This open label trial used a 3+3 design. Cisplatin and berzosertib were each administered intravenously on separate, sequential days for two continuous weeks [day (D) 1 and 8; D2 and 9 respectively], together with veliparib orally twice daily during IV therapy and for 24 hours after (D1-3 and 8-10) in 21-day cycles. Prior platinum and PARP inhibitor therapy were permitted. Tumor expression of DNA damage repair (DDR) biomarkers was assessed at the MTD using validated, quantitative immunofluorescence assays. Results: Fifty-three patients (pts) enrolled, 46 pts evaluable for response. The MTD and RP2D dose is cisplatin 40 mg/m2 D1 and D8, berzosertib 210 mg/m2 D2 and D9, and veliparib 200mg BID (D1-3, D8-10). Three patients achieved a confirmed partial response (PR; 5.6%). A further 2 patients had an unconfirmed PR (breast carcinoma, -30%; HGS carcinoma, -36%). Four responders (3 PR and 1 uPR) received prior platinum. Median time on study: 4 cycles (range 1-25). Genomic data was available on four pts achieving a response: ovarian cancer (BRCA-wildtype, ATM unknown; 25 cycles), breast carcinoma (ATM mutation; 14 cycles), SCC of the tongue (Chek2 mutation; 20 cycles), and HGS carcinoma (ATM/BRIP1 mutation; 4 cycles). Twenty-six pts (56.5%) had stable disease. Thirty-five patients (66.0%) required dose reduction in at least 1 agent, most commonly veliparib (25; 47.2%). Most common grade 3 and 4 adverse events were related to myelosuppression: anemia (20; 37.7%), thrombocytopenia (17; 32.1%), leukopenia (13; 24.5%), neutropenia (12; 22.6%), and lymphopenia (11; 20.8%). Ongoing pharmacodynamic analyses of tumor biopsies collected on C1D1 (post-veliparib/cisplatin) and C1D9 (post-veliparib/cisplatin/M6620) have demonstrated a combination-induced increase in RAD51, indicative of replication stress. Conclusions: The BVP combination shows anti-tumor activity in HR-compromised tumors and M6620 further increases the DDR response elicited by combination cisplatin/veliparib. Citation Format: Geraldine O'Sullivan Coyne, Khanh T. Do, Shivaani Kummar, Naoko Takebe, Sarina Piha-Paul, Richard Piekarz, Deborah Wilsker, Brandon Miller, Katherine Ferry-Galow, Ralph Parchment, Lamin Juwara DNP, Mary Jane Ong, Arjun Mittra, James H. Doroshow, Alice P. Chen. Phase I trial of the triplet berzosertib (M6620, VX-970), veliparib and cisplatin (BVP) in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT115.

NCI’s national treatment trial networks: Experience and adaptations during COVID-19.

1562 Background: The National Cancer Institute supports several national trial networks which responded rapidly to the COVID-19 pandemic to overcome operational barriers to clinical cancer research. The National Clinical Trials Network (NCTN) focuses on late phase treatment trials, while the Experimental Therapeutics Clinical Trials Network (ETCTN) conducts early phase treatment trials. We report findings on the experience and adaptations of these networks during COVID-19. Methods: Using 2019 and 2020 accrual data, we analyzed changes in accrual levels and demographics. We also evaluated changes in trial activation numbers and timelines. In July 2020, we surveyed 255 investigators from academic and community sites to assess changes in research practices and get feedback on modified processes implemented by NCI to address trial conduct during the pandemic. Results: Accrual across the NCTN and ETCTN fell significantly in mid-March 2020, dropping from a weekly average of 307 patients in February to 169 the week of March 23-29. Accrual began to recover in June and July but did not return to pre-pandemic levels until September. Accrual in November and December 2020 followed the patterns seen in 2019, with short-term drops around major holidays. Non-White participants were enrolled to NCTN and ETCTN trials at similar monthly rates throughout 2019 and 2020, with slightly higher overall enrollment in 2020 (23.7% vs. 22.7%). New trials continued to be developed and activated throughout 2020. Between 2017 and 2019, an average of 71 trials were activated per year (NCTN = 46, ETCTN = 25), compared to 84 activated in 2020 (NCTN = 58, ETCTN = 26). The average time to trial activation was similar or slightly longer in 2020 compared to 2019. The investigator survey yielded 111 responses (43.5% response rate). 43% of respondents’ sites paused enrollment to phase 1 trials during the pandemic, compared to 18% for phase 3 trials. Many sites temporarily stopped opening new trials and processing specimens. Sites were more likely to keep enrolling to trials offering clear potential benefit and pause complex trials that required more patient contact. Respondents attributed some of the decline in accrual to a reduction in overall patient volume, increased patient concerns, and reduced research staff on site. Respondents were asked to rate the usefulness of modified trial processes NCI put in place during the pandemic. Telehealth was rated most useful (avg. 4.6/5), followed by shipping oral IND agents to enrolled patients (4.5/5), remote informed consent (4.2/5), coordinating care with local providers (3.9/5), and remote auditing (3.7/5). Conclusions: The cancer trials community has an opportunity to learn from working through the challenges of COVID-19. NCI will seek to continue and expand on modifications to clinical trial processes that have the potential to improve operational efficiency, reduce cost, and help bring trials to more patients.

P10015/SARC033: A phase 2 trial of trametinib in patients with advanced epithelioid hemangioendothelioma (EHE).

11503 Background: EHE is a rare vascular cancer arising in liver, lung, soft tissue and bone. The natural history of metastatic disease varies considerably from indolent growth over years to rapid growth with fatal outcome in months. Treatment of patients (pts) with metastatic EHE with antiangiogenic therapy induces tumor response in a minority of pts, and median PFS is 6-12 months. TAZ-CAMTA1 translocation results in activation of MAPK pathway and is an oncogenic driver in EHE. We sought to evaluate the effect of MEK inhibition using trametinib in pts with unresectable EHE. Methods: A phase 2 trial of trametinib 2 mg daily was conducted in pts with EHE though the Experimental Therapeutics Clinical Trials Network supported by NCI in collaboration with SARC. Additional support was provided by the EHE Rare Cancer Charity and the EHE Foundation. Pts had to have evidence of objective tumor progression or EHE-related pain requiring narcotics for relief prior to enrollment. Presence of TAZ-CAMTA1 translocation was analyzed by fusion-FISH after enrollment. Primary trial endpoint was objective response rate (ORR) per RECIST1.1 with at least 1 objective response required in the 1st 13 pts to expand enrollment to 27. The trial was amended after stage 1 to continue enrollment to 27 pts with TAZ-CAMTA1 detected by FISH with goal of >4 objective responses in this group. Secondary objectives were PFS and OS rates, safety and change in pt-reported global health and pain scores per PROMIS questionnaires. Results: 43 pts were enrolled between 6/2017 – 9/2020 across 10 sites and 41 started therapy. TAZ-CAMTA1 fusion was detected in 26, not detected in 7, test failed in 5 and was not performed due to insufficient tumor in 5. Median pt age was 54 (range 22-81 yrs) and 11 were >65 yrs; 25 were female; ECOG was 0 in 23, 1 in 16 and 2 in 3 pts. Most pts experienced reduction in tumor size. ORR per RECIST was 7% (3/41); in pts with TAZ-CAMTA1 detected, the ORR was 0% (0/26). Mean pain intensity and interference scores had a statistically significant improvement and global quality of life scores did not statistically change after 4 weeks of therapy. 17 pts remained on treatment > 6 months and 7 > 12 months. 25 pts stopped trametinib due to EHE progression, 6 died during treatment, 6 withdrew from treatment, 3 stopped drug due to adverse event and 1 is on treatment. The most common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea, alopecia and edema; Grade >3 AEs included anemia, dyspnea, hypoxia, hypotension, syncope and dermatitis. Conclusions: To our knowledge, this is the largest prospective clinical study focused on pts with EHE. Although the trial did not meet the ORR goal, stable disease > 6 months was seen in 40% of pts, and EHE-related pain improved on treatment. Trametinib was associated with expected cutaneous and GI adverse effects. Additional pt-reported outcomes and biomarkers of inflammation are undergoing analysis. Clinical trial information: NCT03148275.

A randomized phase II study comparing cisplatin and gemcitabine with or without berzosertib in patients with advanced urothelial carcinoma.

4507 Background: Cisplatin with gemcitabine (CG) remains the standard upfront chemotherapy regimen for metastatic urothelial cancer (mUC). Preclinical synergy was noted between cisplatin and berzosertib, a selective ATR inhibitor. The current study sought to determine if the combination of berzosertib and CG could improve clinical outcomes in mUC. Methods: An open-label, randomized study was conducted across 23 centers in the United States through the Experimental Therapeutics Clinical Trials Network of the National Cancer Institute. Key eligibility criteria included confirmed mUC, no prior cytotoxic therapy for metastatic disease, ≥ 12 months since perioperative therapy and eligibility for cisplatin based on standard criteria. Patients (pts) were randomized to receive either CG alone (control arm) or CG plus berzosertib (experimental arm). In the control arm, 70 mg/m2 of cisplatin was given on day 1 and gemcitabine at 1000 mg/m2 on days 1 and 8 of a 21-day cycle. In the experimental arm, 60 mg/m2 of cisplatin was given on day 1, gemcitabine at 875 mg/m2 on days 1 and 8 and berzosertib at 90 mg/m2 on days 2 and 9 of a 21-day cycle. The primary endpoint of the study was progression-free survival (PFS), with secondary endpoints including response rate (RR), overall survival (OS) and toxicity. Results: A total of 87 pts (median age 67; M:F 68:19) were randomized; 41 pts received CG alone while 46 received CG with berzosertib. Visceral metastases were present in 49% of pts and 52%, 45% and 3% of pts were Bajorin risk 0, 1 and 2, respectively. Median PFS was 8.0 months for both arms (Bajorin risk adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 0.72-2.08). RR was 54%(4 CR, 21 PR) in the CG with berzosertib arm and 63% (4 CR, 22 PR) in CG alone arm (P = 0.66). Median OS was shorter with CG with berzosertib as compared to CG alone (14.4 versus 19.8 months; Bajorin risk adjusted HR 1.42, 95%CI 0.76-2.68). Notably higher rates of grade 3/4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with CG plus berzosertib compared to CG alone. Higher rates of toxicity-related discontinuation were seen in the experimental arm (24% vs 15%), and the median cumulative cisplatin dose in the experimental arm was 250 mg/m2, as compared to 370 mg/m2 in the control arm (P < 0.001). Conclusions: No improvement in PFS was observed with the addition of berzosertib to CG, and a trend towards inferior survival was observed. These results suggest caution in reducing the starting dose of cytotoxic therapy to accommodate addition of a myelosuppressive agent, as in the experimental arm of this study. Clinical trial information: NCT02567409.

A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO).

TPS2676 Background: Nivolumab is an anti-PD1 monoclonal antibody approved for treatment of an increasing number of solid tumors and hematological malignancies. However, patients (pts) with history of autoimmune disorders are excluded from the majority of clinical trials testing immune-checkpoint inhibitors (ICI) such as anti-PD1/anti-PD-L1 antibodies. Consequently, the risks of flare ups, worsening of pre-existing autoimmune disorders or risk of de-novo immune related adverse events (irAEs) in pts with dysfunctional immune systems and tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to pts with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis and other autoimmune disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in pts with autoimmune diseases and advanced malignancies (NCT03816345). The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in pts with autoimmune disorders and advanced malignancies. Secondary objectives are to evaluate the antitumor efficacy; the impact of nivolumab on the autoimmune disease severity indices; and to explore potential biomarkers of response, resistance, or toxicity for each of the autoimmune disease-specific cohorts. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced or metastatic malignancies in which ICI are approved or have shown clinical activity. Key overall exclusion criteria include prior therapy with anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 pts will be included in each disease cohort at each severity level (max 36 pts per cohort). Primary endpoints are dose-limiting toxicities, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response per RECIST1.1; progression free and overall survival; and cohort specific tumor tissue, blood, and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is enrolling pts through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN), Early Drug Development Opportunity Program (EDDOP), and Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP) sites. Clinical trial information: NCT03816345.

Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell activation and costimulation such as PD-1, HLA-DR, and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T-cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T-cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GVL outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01822509.

A Phase I Study of Anti-ICOS Antibody MEDI-570 for Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Angioimmunoblastic T-Cell Lymphoma (AITL) (NCI-9930)

Background:T-follicular helper (TFH) cells are a novel CD4+ T-cell subset that participates in germinal center maintenance/proliferation. Proliferation of TFH is a postulated mechanism of pathogenesis for T-cell lymphomas (AITL, PTCL and others). The inducible T-cell costimulator (ICOS) is highly expressed in TFHand hence in AITL, PTCL FH type, and some cutaneous T cell lymphomas (CTCL) and follicular lymphomas (FL). MEDI-570 is a human afucosylatedIgG1 kappa monoclonal antagonistic antibody directed against ICOS, which binds to and eliminates ICOS expressing cells in preclinical in vivo models. We investigate the safety, pharmacokinetics (PK) and clinical activity of ICOS blockade by MEDI-570 in T-cell lymphomas. Methods: NCI-9930 is a Phase I study of MEDI-570 in R/R malignant lymphomas. It is a 3+3 study design that evaluated 5 dose levels . MEDI-570 was administered intravenously (IV) every 3 weeks for 12 cycles. Eligibility criteria included: age >18 years, ECOG <2, diagnosis of R/R PTCL, AITL, CTCL, mycosis fungoides, or FL, that have received and are refractory to at least 1 line of therapy (at least 2 lines of therapy and post autologous cell transplantation for FL), adequate organ functions and CD4+ T-cells >200 cells/uL (>100 for AITL). Primary endpoints are safety of MEDI-570, dose limiting toxicities (DLT)s and its recommended phase 2 dose (RP2D). Secondary endpoints include: pharmacokinetics (PK), overall response rate (ORR) based on Lugano classification and progression-free survival (PFS). Exploratory endpoints include various correlative studies. This study is supported by the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN) and Early Drug Development Opportunity Program (EDDOP) (NCT02520791). Results: As of June 2020, the dose escalation phase has been completed. Patients were enrolled and evaluable for safety and efficacy. Median age is 63 (range: 29-80), female/male ratio=5/13, histologic types consisted in AITL (n= 12, 71%), PTCL NOS (n=3, 18%) and CTCL (n=2, 12%). The median number of prior therapies were 7.5 (1 - 16), stage III/IV in 83%, prior autologous HCT in 18%. There were 4 partial remissions (PR) and 7 with stable disease (SD), all patients with AITL. Two patients (1 PR and 1 SD) remain on treatment. One patient completed treatment and remains in a stable PR for over a year without further treatment. One patient in PR underwent allogeneic hematopoietic transplantation (HCT) and remains in remission. The most common grade 3/4 AEs were decreased CD4+ T-cells as expected anemia (12%), hypophosphatemia (12%), thrombocytopenia (6%), infusion related reactions (6%). No DLTs were reported, and the maximum tolerated dose was not established. Initial PK analyses demonstrated that MEDI-570 systemic exposure increased in a dose-dependent manner, and a RP2D was determined. Peripheral blood flow cytometry analysis of T-cell subsets showed that MEDI-570 caused a rapid and sustained decrease in CD4+ T-cells. It also resulted in reductions in circulating of certain ICOS+ T-cells, especially on days 7-21 post treatment. Conclusion: MEDI-570 was safe, well tolerated and showed promising clinical activity in poor-risk refractory and heavily pretreated AITL. A RP2D was established. MEDI-570 results in sustained reduction of the targeted ICOS+T lymphocytes. The study continues enrolling in the expansion phase. Disclosures Chavez: Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy; Verastem: Consultancy; Epizyme: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy. William:Dova: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Guidepoint Global: Consultancy. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Smith:Pharmacyclics: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; Acerta: Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy. Prica:astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria. Zain:Kyowa Kirlin: Research Funding; Mundai Pharma: Research Funding; Seattle Genetics: Research Funding. Glenn:Genentech: Research Funding. Mehta-Shah:Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Kyowa Kirin: Consultancy; Innate Pharmaceuticals: Research Funding; Celgene: Research Funding; Genetech: Research Funding; C4 Therapeutics: Consultancy; Bristol Myers-Squibb: Research Funding. Boutrin:Astrazeneca: Current Employment, Current equity holder in private company. Zhao:Astrazeneca: Current Employment, Current equity holder in private company. Cheng:Astrazeneca: Current Employment, Current equity holder in private company. Standifer:Astrazeneca: Current Employment, Current equity holder in private company. Carlesso:Astrazeneca: Current Employment, Current equity holder in private company. Siu:Shatthucks: Research Funding; Symphogen: Consultancy, Research Funding; Tessa: Consultancy; Treadwell Therapeutics: Consultancy, Current Employment; Pfizer: Research Funding; Voronol: Consultancy; Rubius Therapeutics: Consultancy; Abbvie: Research Funding; Agios: Current equity holder in publicly-traded company; Arvinas: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy, Research Funding; Bayer: Research Funding; Boerhinger-Ingelheim: Research Funding; Bristol-Myers Squibb: Research Funding; Glaxo Smith Kline: Research Funding; Intensity Therapeutics: Research Funding; Navire: Consultancy; Novartis: Research Funding; Oncorus: Consultancy; Mirati: Consultancy, Research Funding; Roche/Genentech: Consultancy; Relay Therapeutics: Consultancy; Roche: Consultancy; Merck: Consultancy.

Abstract PO-092: Expanded access trial of tocilizumab in COVID19+ hospitalized cancer patients

Abstract Introduction: Emerging data from the COVID-19 pandemic suggest that an IL6-mediated cytokine release syndrome (CRS) may contribute to disease severity. Tocilizumab (Toci), an anti-IL6 receptor antibody, is FDA approved for the treatment of chimeric antigen receptor T cell-associated CRS for patients (pts) as young as 2 years of age. Phase 3 randomized testing of toci in pts with severe COVID-19 disease is ongoing. Cancer pts infected with SARS-CoV-2 are at risk for life-threatening or fatal complications. Outcomes are particularly dismal for those with hematologic malignancies or lung cancer. Due to disease and treatment-related complications, cancer patients may not be eligible for enrollment on COVID-19 directed studies, including the aforementioned randomized phase 3 study of toci. Furthermore, access to clinical trials is frequently restricted to those who are adults; however, children with cancer may also be predisposed to developing more severe complications from COVID-19. Improving access to clinical trial enrollment for vulnerable, minority, and underserved populations at increased risk of complications from COVID-19 is imperative. Methods: We developed a multicenter, single-arm, open-label, expanded-access treatment study to provide toci to cancer pts with COVID-19. Coordinated through the National Cancer Institute, Cancer Therapy Evaluation Program, and the Division of Cancer Treatment and Diagnosis, this expanded-access trial is being conducted to provide clinical trial access to this potentially beneficial therapy in cancer pts and to collect data on clinical outcomes. The primary objective is to enhance access to toci for cancer patients who cannot participate in the randomized phase 3 toci trial with a specific emphasis on enrollment of those who belong to high-risk and minority populations and children. Hospitalized cancer subjects > 2 years of age with COVID-19 respiratory compromise may be eligible to receive toci. Treatment will allow for up to two doses of toci and will also evaluate the efficacy of a lower dose of toci in those who are not intubated. Concurrent receipt of investigational cancer and/or antiviral therapy and other supportive therapies is permitted. Exploratory objectives will include analysis of inflammatory cytokines, monitoring of SARS-CoV-2 viral load, and determination of pharmacokinetics of toci to facilitate exposure-response analysis. Results: This trial was officially activated on May 28, 2020, and is being opened at multiple sites across the United States from the National Cancer Institute’s Community Oncology Research Program, the National Clinical Trials Network, and the Experimental Therapeutics Clinical Trials Network. Updates will be presented at the AACR Virtual Meeting: COVID-19 and Cancer. Conclusions: Targeting an unmet need, this trial provides a prospective mechanism for tocilizumab access and clinical outcome collection in cancer patients with severe COVID-19 disease. Citation Format: Nirali N. Shah, Percy Ivy, Rebecca Enos, Matthew J. Boron, Rodney Howells, Boris Freidlin, Carmen Allegra, Margaret M. Mooney, Worta McCaskill-Stevens, James H. Doroshow, Richard F. Little. Expanded access trial of tocilizumab in COVID19+ hospitalized cancer patients [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-092.

Abstract CT043: A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study

Abstract Background: BTCs are aggressive cancers with a poor prognosis. In preclinical models, MEK inhibition modulates the tumor immune microenvironment and enhances responses to programmed death-ligand 1 (PD-L1) inhibition. We report a randomized, open-label, multicenter phase 2 trial of atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor) in BTC (NCT03201458). Methods: Eligible patients had advanced BTC [intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC)], with 1-2 lines of prior therapy in the metastatic setting, measurable disease by RECIST v1.1, and ECOG performance status ≤1. Patients randomized to Arm A received atezolizumab 840 mg IV Q2w. Patients randomized to Arm B received oral cobimetinib 60 mg daily (21 days on/7 days off) plus atezolizumab 840 mg IV Q2w. The primary endpoint was progression free survival (PFS) using the Kaplan-Meier method and compared between groups under the assumption of Cox proportional hazards, stratified for primary tumor site. Secondary endpoints included objective response rate (ORR), safety and tolerability, and overall survival (OS). Results: 86 patients were enrolled at 23 centers in the United States; 77 patients were randomized and received at least one dose of study therapy (Arm A: n=37, ICC=21, ECC=7, GBC=11; Arm B: n=38, ICC=22, ECC=8, GBC=8). Median age was 63 (range 44-86), and 48 (62%) were female. The trial met its primary endpoint, with a median PFS of 3.65 months (cobimetinib+atezolizumab) vs 1.87 months (atezolizumab monotherapy) (p=0.027). OS data are not mature at the time of analysis. There was 1 PR (3.2%), 13 SD (41.9%), and 17 PD (54.8%) in the combination arm and 1 PR (2.9%), 10 SD (29.4%), and 23 PD (67.6%) in the atezolizumab monotherapy arm. Two patients in the combination arm remain on therapy 15+ months from enrollment. One patient in each treatment arm had known mismatch repair deficiency (MMRd), of whom 1 had PD as a best response and the other withdrew prior to response evaluation. Grade 3-4 treatment-related adverse events were similar in both arms, and there were no treatment-related deaths. 4 (10%) of patients receiving atezolizumab monotherapy and 8 (22.2%) receiving cobimetinib+atezolizumab discontinued therapy due to adverse events. Changes in tumor CD8, CD4, FoxP3, PDL1, and MHC expression from paired tumor biopsies will be presented at the conference. Conclusions: We report the first randomized trial of immunotherapy in BTC. The combination of atezolizumab plus cobimetinib met its primary endpoint and significantly prolonged PFS as compared to atezolizumab monotherapy in BTC. The combination of atezolizumab and cobimetinib had manageable toxicity and warrants further investigation in BTC. Citation Format: Mark Yarchoan, Leslie Cope, Robert A. Anders, Anne Noonan, Laura W. Goff, Lipika Goyal, Jill Lacy, Daneng Li, Anuj Patel, Aiwu R. He, Ghassan Abou-Alfa, Kristen Spencer, Edward Kim, Stephanie Xavier, Amanda Ruggieri, S. Lindsey Davis, Autumn McRee, Paul Kunk, Qingfeng Zhu, Andrea Wang-Gillam, Andrew Poklepovic, Helen Chen, Elad Sharon, Gregory B. Lesinski, Nilo Azad. A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT043.

Abstract CT249: A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO)

Abstract Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have rapidly become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for treatment of melanoma, lung, renal cell, head and neck squamous, urothelial and increasing number of other solid and hematological malignancies. However, patients with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flare ups and worsening of pre-existing autoimmune disorders in patients with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to patients with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis and others autoimmune disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in patients with autoimmune diseases and advanced or metastatic solid tumors. The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in patients with autoimmune disorders and advanced or metastatic solid tumors. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced or metastatic solid tumors in which ICI are approved or have shown clinical activity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Key overall exclusion criteria include prior therapy with an anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 patients will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities defined for each autoimmune disease-specific cohort, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is currently enrolling patients in the participating sites through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345. Citation Format: Ecaterina E. Ileana Dumbrava, Maria Suarez-Almazor, Jeane Painter, Tanner M. Johanns, Michael L. Dougan, Laura Cappelli, Yinghong Wang, Clifton Bingham, Sarthak Gupta, Blake M. Warner, Osama Rahma, Jarushka Naidoo, Patrick A. Ott, David A. Hafler, Harriet Kluger, Arezou Khosroshahi, Rafeh Naqash, Lorinda Chung, Tamiko R. Katsumoto, Shivaani Kummar, Hussein Tawbi, Elad Sharon. A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT249.