Dose Expansion Cohort Research Articles

Updated Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

Updated Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

Cevostamab Monotherapy Continues to Show Clinically Meaningful Activity and Manageable Safety in Patients with Heavily Pre-Treated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study

Cevostamab Monotherapy Continues to Show Clinically Meaningful Activity and Manageable Safety in Patients with Heavily Pre-Treated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study

First in Human Study of an on/Off Switchable CAR-T Cell Platform Targeting CD19 for B Cell Malignancies (CLBR001 + SWI019)

First in Human Study of an on/Off Switchable CAR-T Cell Platform Targeting CD19 for B Cell Malignancies (CLBR001 + SWI019)

NIMBLE: A Phase I/II Study of AZD0466 Monotherapy or in Combination in Patients with Advanced Hematological Malignancies

NIMBLE: A Phase I/II Study of AZD0466 Monotherapy or in Combination in Patients with Advanced Hematological Malignancies

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

A Phase 1/2 Dose-Escalation and Dose-Expansion Study of the Safety and Efficacy of Anti-CD7 Allogeneic CAR-T Cells (WU-CART-007) in Patients with Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)/ Lymphoblastic Lymphoma (LBL)

BackgroundT-ALL/LBL represent a class of devastating hematologic cancers with high rates of relapse and mortality in both children and adults. Despite intensive multi-agent chemotherapy regimens, fewer than 50% of adults and 85% of children with T-ALL survive beyond five years. For those who relapse after initial therapy, salvage regimens induce remissions in only ~20-30% of cases, and survival is dismal. T-ALL/LBL is a genetically diverse group, but with universal overexpression of CD7, making this a suitable target for immunotherapy. Despite the success of CAR-T cells in B-cell malignancies, CAR-T cell development in T-cell malignancies has proven challenging due to fratricide and high risk of contamination of the genetically modified CAR-T product with the patient's malignant T cells. WU-CART-007 is a CD7-directed, genetically modified, allogeneic, ‘off the shelf’, fratricide-resistant chimeric antigen receptor (CAR) T-cell product for the treatment of CD7+ve hematologic malignancies.MethodsThis multicenter, open-label, dose-escalation, Phase 1/2 study (NCT#04984356) of WU-CART-007 in patients ≥ 12 years old, with relapsed or refractory T-ALL/LBL is designed to characterize the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD)/maximum administered dose (MAD; if no MTD defined) (Phase 1), and to investigate the preliminary anti-tumor activity, as measured by objective response rate (ORR) and duration of response (DOR) (Phase 2). Phase 1 is comprised of a dose escalation segment and will proceed according to a standard 3+3 design testing up to 4 dose levels from 1 to 9 x 10 8 cells. Adolescent patients, ages 12-17, will be eligible for enrollment in Phase 1 Dose Escalation beginning at Dose level 3 and 4, and during Phase 2 Cohort Expansion. Upon reaching the MTD and/or RP2D, the Phase 2 portion comprised of the cohort expansion segment will be launched. A Simon's optimal two-stage design will be implemented to enroll patients (an interim analysis for futility in the first stage and the final analysis in the second stage) for Phase 2 dose expansion cohort to confirm safety and explore preliminary efficacy. All patients will receive a single infusion of WU-CART-007 cells on day 1 following a lymphodepleting conditioning therapy consisting of fludarabine and cyclophosphamide on days -5 to -3. Patients will be hospitalized for a minimum of 7 days following WU-CART-007 administration. Response will be assessed on Cycle 1 Day 28 (± 1 days), and at Months 3, 6, 12, and 24, by bone marrow aspirate and biopsy and PET/CT if indicated. Response will be defined as per modified NCCN Guidelines Version 2.2020. DisclosuresGhobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Locke: Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Legend Biotech: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Takeda: Consultancy, Other; Wugen: Consultancy, Other; Cowen: Consultancy; Umoja: Consultancy, Other; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Maude: Wugen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Davidson-Moncada: Wugen: Current Employment. Cooper: Wugen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties; NeoImmune Tech: Patents & Royalties; RiverVest: Consultancy.

Phase I Dose-Escalation Study of Venetoclax Plus BEAM Followed By Autologous Stem Cell Transplant (ASCT) for Chemoresistant or High-Risk Relapsed/Refractory Non-Hodgkin Lymphoma (NHL)

Phase I Dose-Escalation Study of Venetoclax Plus BEAM Followed By Autologous Stem Cell Transplant (ASCT) for Chemoresistant or High-Risk Relapsed/Refractory Non-Hodgkin Lymphoma (NHL)

ARC-12: Phase 1/1b Study to Evaluate Safety and Tolerability of AB308 + Zimberelimab (AB122) in Advanced Malignancies

Background: PD-(L)1 pathway inhibitors have demonstrated durable clinical benefit in both solid tumors and hematologic malignancies; however, as less than 1/3 of patients respond to anti-PD-(L)1 monotherapy, combination therapies may be needed for improved response rates and survival. T cell Immunoglobulin and ITIM domain (TIGIT) is expressed on activated T cell and natural killer (NK) cell subsets; TIGIT-CD155 binding suppresses T and NK cell function and inhibits the antitumor immune response. AB308, an Fc-enabled anti-TIGIT humanized IgG1 monoclonal antibody (mAb), has reversed TIGIT-CD155-mediated T cell inhibition in preclinical models. ARC-12 will assess whether TIGIT pathway blockade by AB308 can augment zimberelimab (zim; anti-PD-1 mAb) activity in patients with solid and hematologic malignancies.Study Design and Methods: ARC-12 is a phase 1/1b, first-in-human, open-label, dose-escalation study of AB308 + zim in patients with advanced solid tumors or hematologic malignancies. Dose expansion cohorts include relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). For the dose-escalation, eligible adults have solid tumors for which no standard-of-care therapy exists or have pathologically-confirmed R/R non-Hodgkin lymphoma (NHL) and have not received or are ineligible for allogeneic stem cell transplant or adoptive cell transfer; ≤5 lines of prior systemic therapy; ≥1 measurable lesion per RECIST (solid tumors) or Lugano Classification (NHL) criteria; and ECOG performance score of 0-1. As shown in the figure, patients will receive AB308 + zim intravenously (IV) once every 3 weeks (Q3W; Part A) or once every 4 weeks (Q4W; Part B). In Part A, the first 6 patients of Cohort 1 will follow 3+3+6 rules, allowing for AB308 dose adjustment if dose-limiting toxicities (DLTs) warrant; all other dose-escalation cohorts will use 3+3 rules. After the Cohort 2 DLT period has been cleared, Part B enrollment will begin in parallel with Part A to determine the recommended dose for expansion (RDE) for AB308 + zim for both the Q3W (Part A) and Q4W (Part B) schedules. Each part can independently proceed to dose-expansion once the RDE is determined for that dose schedule. In the dose-expansion, patients will be enrolled into disease-specific cohorts for non-small cell lung cancer (NSCLC), melanoma, gastrointestinal cancer, cervical cancer, and hematologic malignancies (DLBCL or MM). AB308 + zim may be dosed on either a Q3W or Q4W schedule; all patients in each expansion cohort will receive the same dose schedule. For both the dose-escalation and dose-expansion, the primary endpoints assess safety and tolerability of AB308 + zim; secondary endpoints include pharmacokinetics (PK), immunogenicity, and objective response rate for AB308 + zim. Additional secondary endpoints in the dose-expansion are disease control rate and duration of response. Safety and efficacy data will be analyzed using summary statistics and Kaplan Meier estimates as appropriate; PK parameters will be estimated using noncompartmental methods. ARC-12 is actively recruiting at sites in the United States (NCT04772989). [Display omitted] DisclosuresAilawadhi: Pharmacyclics: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Research Funding; Ascentage: Research Funding; Genentech: Consultancy; AbbVie: Consultancy; BMS: Consultancy, Research Funding; Xencor: Research Funding; Janssen: Consultancy, Research Funding; Medimmune: Research Funding; Cellectar: Research Funding; Karyopharm: Consultancy; Beigene: Consultancy; GSK: Consultancy, Research Funding. Foster: Arcus Biosciences, Inc.: Current Employment. Ryba: Arcus Biosciences, Inc.: Current Employment. Scharville: Arcus Biosciences, Inc.: Current Employment. El-Baghdady: Arcus Biosciences, Inc.: Current Employment. OffLabel Disclosure:AB308 and zimberelimab (AB122) are in clinical development and are not approved in the United States for the use under discussion.

Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion–Positive Metastatic Non–Small Cell Lung Cancer

Metastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target EGFRex20ins mutations. To evaluate treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC. This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreated EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treated EGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort). Mobocertinib 160 mg once daily. The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety. Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash. In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile. ClinicalTrials.gov Identifier: NCT02716116.

Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study

Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome. This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621. Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient. Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions. Trillium Therapeutics.

Concentration-QT modelling in early clinical oncology settings: Simulation evaluation of performance.

Concentration-QT modelling (C-QTc) of first-in-human data has been rapidly adopted as the primary evaluation of QTc interval prolongation risk. Here, we evaluate the performance of C-QTc in early oncology settings (i.e., patients, no placebo or supratherapeutic dose, 3 + 3 designs). C-QTc performance was evaluated across three oncology scenarios using a simulation-estimation approach: (scen1) typical dose-escalation testing six dose levels (n = 21); (scen2) small dose-escalation testing two dose levels (n = 9); (scen3) expansion cohorts at one dose level (n = 6-140). True ΔΔQTc effects ranged from 3ms ("no effect") to 20 ms ("large effect"). Performance was assessed based on the upper limit of the ΔQTc two-sided 90% CI against a threshold of 10 or 20 ms. The performance against the 10ms threshold was limited based on C-QTc data from typical dose escalation (scen1) and acceptable performance was observed only for relatively large expansions (n ≥ 45; scen3). Performance against the 20 ms threshold was acceptable based on C-QTc data from a typical dose escalation (scen1) or dose expansion cohort n > 10 (scen3). In general, pooling C-QTc data from dose escalation and expansion cohorts substantially improved the performance and reduced the ΔQTc 90% CI width. C-QTc performance appeared limited using a 10ms threshold, but acceptable against a 20 ms threshold. Selection of threshold may be informed by the benefit-risk balance in a specific disease area. Acceptable precision (i.e., confidence intervals) of the estimated ΔQTc, regardless of its magnitude, can be facilitated by pooling data from dose escalation and expansion cohorts.

964MO Entinostat, nivolumab and ipilimumab in advanced HER2-negative breast cancer (ETCTN-9844)

In murine models of breast cancer the histone deacetylase inhibitor entinostat increases CD8+ effector: FoxP3+ regulatory T-cell ratios (CD8/FoxP3), and improves the efficacy of immune checkpoint inhibitors. We identified a recommended phase II dose (RP2D) for the combination of entinostat, nivolumab and ipilimumab (ETCTN-9884, manuscript submitted). We report combined safety and efficacy results of participants with HER2-negative breast cancer treated in dose escalation (n=6) and expansion cohorts treated at the RP2D (n=18). Participants received entinostat PO 5mg weekly x 2 (run-in), then 3-5mg weekly entinostat PO, 3mg/kg q2 weeks nivolumab, and 1mg/kg q6 weeks ipilimumab IV (max 4 doses ipi, RP2D). Primary endpoint: Safety (CTCAE v5). Secondary endpoints: Change in tumor CD8/FoxP3 ratio (integrated biomarker); Objective response rate (ORR). We obtained tissue samples at baseline, after 2 week run-in, and after 8 weeks of combination therapy and completed immunohistochemical staining for CD8, FoxP3 and PD-L1. Blood samples at each timepoint were obtained and Luminex analysis for global changes in plasma cytokine expression was performed. Amongst 24 participants [12 hormone receptor-positive (HR+), 12 triple-negative (TNBC)], median age was 54.5 years (range 38-77) and median prior therapies 6.5 (range 1-13). Median cycles received was 2 (range 1-17). Grade 3/4 AEs included anemia (N=4, 17%), decreased neutrophil count (N=3, 13%), and increased lipase (N=2, 8%). Most common immune-related (ir) AEs included rash (N =7, 29%), hypothyroidism (N =5, 21%), and pneumonitis (N=2, 8%). ORR by RECIST (v1.1) was 30% (6/20 evaluable), and by irRECIST was 20% (4/20 evaluable), including a complete response in a participant with TNBC. The combination of entinostat, nivolumab and ipilimumab at the RP2D was associated with expected (ir) AEs in advanced HER2-negative breast cancer. An ORR of 30% suggests this combination should be evaluated further. Correlative analyses from serial biospecimens pre- and post-therapy to evaluate the immune response and landscape will be presented.

Abstract CT012: TRX-E-002-1 in treatment-refractory ovarian cancer: Final phase 1 study results from the dose-escalation and dose-expansion cohorts

Abstract Introduction: For women with advanced ovarian cancer survival outcomes with standard cytotoxic chemotherapy are poor and are thought to reflect the existence of drug-resistant ovarian cancer stem cells. TRX-E-002-1 (Cantrixil), a novel third generation benzopyran molecule has been shown to be effective in a mouse model of recurrent chemotherapy-resistant ovarian cancer. We present the final results of a phase I progressive design trial (Part A dose escalation, Part B dose expansion) of Cantrixil (NCT02903771). The objectives were to establish maximum tolerated dose (MTD) when given in combination with chemotherapy, and to evaluate safety, tolerability and anti-tumour activity of intraperitoneal (IP)-administered Cantrixil. Methods: Women who had completed ≥2 prior regimens and whose disease was platinum-refractory, platinum-resistant or who had documented intolerance to platinum therapy, were eligible. Treatment comprised up to eight 3-week cycles. In the first 2 cycles, patients were dosed weekly with Cantrixil as monotherapy after which investigators were allowed to initiate pre-defined standard intravenous chemotherapy regimens (cycles 3-8). All patients were followed up for 3 months after the end of treatment. Results: Of 32 patients enrolled, 25 received ≥1 Cantrixil dose; 6 patients (24%) completed all 8 treatment cycles. Patients (92% Caucasian, mean age 62.5 years) had a median of 2 prior lines of platinum therapy and a median of 3 prior lines of anticancer therapies (including anti-VEGF; n=13, 52% and PARPi; n=6, 24%). Platinum sensitivity: refractory (n=3,12%), resistant (n=17, 68%), sensitive (n=5, 20%). In Part A (n=11), an MTD of 5mg/kg was established on the dose-limiting toxicity of ileus (n=2) and safety signals of bowel obstruction (n=3) and abdominal pain (n=2). The pharmacokinetic profile was multi-exponential, with rapid increases in systemic concentration and distribution and a slower elimination phase. Drug accumulation was minimal and was not influenced by co-administration of chemotherapy. Analysis of weight and dose-normalized (to 1 mg/kg) data found no notable trends. Across Parts A and B, 16 patients received ≥1 Cantrixil dose and had a post-baseline efficacy measurement available. The overall response rate was 18%, including one complete response (platinum-resistant; who remains in remission 37.05 months since starting treatment) and two partial responses (one platinum-resistant, one platinum refractory). The median progression free survival was 3.06 months (95% CI:1.28,∞). Conclusion: IP-administered Cantrixil, a first-in-class, dual acting, anti-cancer therapy has encouraging activity in a cohort of difficult to treat patients with persistent epithelial ovarian, fallopian tube or primary peritoneal cancer who have demonstrated resistance to a range of prior treatments. Disease response compares favorably to a figure of 10% for historical controls. Citation Format: Jermaine Coward, Ganessan Kichenadasse, Paul Harnett, Kathleen Moore, Minal Barve, James Garner, Mary Lopresti, Don S. Dizon. TRX-E-002-1 in treatment-refractory ovarian cancer: Final phase 1 study results from the dose-escalation and dose-expansion cohorts [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 CT012.

Abstract CT019: A phase I trial of the combination of the dual RAF-MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Evaluation of efficacy in KRAS mutated NSCLC

Abstract Background KRAS is a known oncogenic driver in non-small cell lung cancer (NSCLC), with KRAS G12C and G12V mutations occurring in ~13% and ~7% of the of NSCLC ( adenocarcinoma subtype). The dual RAF-MEK inhibitor VS-6766 has shown single agent activity against G12V KRAS mutated NSCLC (Guo C et al Lancet Oncology 2020, 21:1478-88). Based on pre-clinical data, we hypothesised that augmented focal adhesion kinase (FAK) signalling is a mechanism of resistance to MEK inhibition and devised the current clinical trial. We have previously reported the safety of an intermittent schedule of the combination of VS-6766 and the FAK inhibitor defactinib and its efficacy in low grade serous ovarian cancer (Shinde et al., AACR 2020). We now report the activity of the combination in KRAS mutated NSCLC. Methods Patients were treated with an intermittent dose of drugs VS-6766 at 3.2 - 4 mg twice a week and defactinib 200 mg twice daily in the dose escalation and expansion cohorts of the study. Both drugs were administered three weeks on/one week off in 28-day cycles. We aim to recruit 20 patients with KRAS mutated NSCLC in an expansion cohort. Results To date, 19 patients with KRAS mutated NSCLC have been treated in the dose escalation and expansion cohorts. All patients had been previously treatment with a PD-1 or PDL-1 targeting immune checkpoint inhibitor. The median age was 64 years (22 - 73), M/F ratio was 7/12, and the median prior lines of treatment was 3. Currently, 17 of 19 patients have had at least one re-staging assessment, 2/17 (12%) patients had a partial response and 10/17 (59%) had stable disease as their best response. Of note, 11/17 (65%) patients had a degree of reduction in size of their tumours and 5/17 (29%) have been treated for 6 months or more with 3 patients still on treatment. Interestingly, 2/2 (100%) of the KRAS G12V NSCLC patients showed a partial response. Conclusions Developing new treatments for non-G12C KRAS mutated NSCLC is an area of unmet need. The combination of VS-6766 and defactinib treatment in cohorts of patients with NSCLC pre-treated with chemotherapy and immunotherapy has shown anti-tumour activity in subsets of patients with KRAS mutated NSCLC, in particular those with tumours harbouring KRAS G12V mutations. A registration-directed study evaluating VS-6766 ± defactinib for treatment of recurrent NSCLC with KRAS G12V mutation (NCT04620330) has been initiated Citation Format: Matthew G. Krebs, Rajiv Shinde, Rozana Abdul Rahman, Rafael Grochot, Martin Little, Jenny King, Joseph Kitchin, Mona Parmar, Alison Turner, Muneeb Mahmud, Christina Yap, Nina Tunariu, Juanita Lopez, Johann S. De Bono, Udai Banerji, Anna Minchom. A phase I trial of the combination of the dual RAF-MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Evaluation of efficacy in KRAS mutated NSCLC [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 CT019.

Abstract 674: A phase I trial of Triapine and Lutetium Lu 177 Dotatate in combination for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

Abstract 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 Lu 177 Dotatate (Lutathera) is a beta- and gamma-emitting radionuclide. Lutathera has been recently FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on NETTER-1 Phase III trial. Despite favorable PFS, and safety profile, the drug has limited cytoreductive capability. NETTER-1 reported 17% ORR. PRRT also doesn't seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer can help improve antitumor activity of Lutathera. Rationale: Triapine is a ribonucleotide reductase (RNR) inhibitor. Radiation is a potent inducer of DNA double-strand breaks (DSBs). Targeting signaling networks involved in DSB repair is a promising approach for enhancing cellular radio sensitivity. RNR is the rate-limiting enzyme in the synthesis and repair of DNA, and it is directly involved in the cellular response to radiation, making RNR-targeted therapy to enhance radiation treatment a rational therapeutic strategy. RNR is the only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. This study will test the hypothesis that triapine is an effective radiation sensitizer which can be safely combined with peptide receptor radionuclide therapy and can improve antitumor activity of Lutetium Lu 177 Dotatate. Method: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in combination for 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 (BOIN design) and dose expansion cohorts. The study will be open through the entire ETCTN. Patients will be treated with 177 lutetium dotatate in combination with Triapene. Triapene will be administered orally from D1-14 with each dose of PRRT. Primary endpoint is to evaluate RP2D. Secondary endpoints are looking into clinical activity (ORR, PFS and OS). We are also evaluating NETEST, a novel blood based predicting as well as prognosticating test. In addition, the study will evaluate baseline somatostatin receptor density, somatic tumor mutations and germline mutations and correlate with clinical outcome. ClinicalTrials.gov Identifier: NCT04234568 Citation Format: Aman Chauhan, Charles Kunos, Riham El Khouli, Jill Kolesar, Heidi L. Weiss, Bill Carson, Mark Kidd, Jan Beumer, Susanne Arnold, Elise Kohn, Lowell Anthony. A phase I trial of Triapine and Lutetium Lu 177 Dotatate in combination for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [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 674.

Abstract CT130: Phase 1 study of the novel immunotoxin MT-5111 in patients with HER-2+tumors

Abstract Background: Engineered toxin bodies (ETBs), composed of an engineered Shiga-like Toxin A subunit genetically fused to an antibody-binding domain, can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other targeted agents. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, also binds to an epitope distinct from trastuzumab and pertuzumab, which may permit combination strategies with other HER2 targeting agents. Methods: The primary objective is to determine maximum tolerated dose (MTD) of MT-5111 monotherapy in adult patients (pts) with advanced HER2+ solid tumors. Secondary objectives are PK, efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study includes the following 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and any other HER2+ tumors. All pts will receive MT-5111 weekly as a 30-min IV infusion in each 21-d treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: As of the data cut in December 2020, 16 pts were treated; cancer types included breast (n=6), gastric (n=1), colon (n=1), gallbladder (n=5), and other solid tumors (n=3). Mean age was 64 years (range, 34-78); 37.5% were male. Pts received a median of 4 prior lines of systemic therapies (range, 1-8). No G4 or G5 TEAEs occurred. Six pts had 11 G3 TEAEs; the most common were increased AST and dyspnea (both n=2). Three pts had tx-emergent serious adverse events (abdominal distension [n=1]; dyspnea [n=2]). Tx-related TEAEs occurred in 8 (50%) pts; the most common was fatigue (n=5, 31.3%) and all were ≤ grade 2 in nature, except for one grade 3 event of dyspnea. No cardiac TEAEs, clinically significant changes in cardiac biomarkers (troponin, electrocardiogram, left ventricular ejection fraction), or cases of capillary leak syndrome were observed. Fifteen pts discontinued with PD; 1 pt in cohort 5 (4.5 µg/kg) is on tx with stable disease. To date, no DLTs have been observed and the MTD has not been reached. One pt in cohort 2 (1 µg/kg) had resolution of all hepatic lesions (sub-centimeter lesions pre-tx) at the end of C8; however, the pt came off study due to clinical progression at the end of C10. PK data for the first 5 cohorts matched simulations based on non-human primate studies. Conclusions: MT-5111 was well tolerated with no clinically significant cardiotoxicity. Continued dose escalations are ongoing. Citation Format: Zev A. Wainberg, Monica M. Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Christine Burnett, Joshua Pelham, Eric T. Williams, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Brian A. Van Tine. Phase 1 study of the novel immunotoxin MT-5111 in patients with HER-2+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 CT130.

A Multicenter Phase I Dose-Finding and Preliminary Efficacy Study of the Histone Deacetylase Inhibitor Romidepsin in Combination with Pegylated Liposomal Doxorubicin for the Treatment of Adults with Relapsed or Refractory Cutaneous and Peripheral T-Cell Lymphomas

IntroductionLiposomal doxorubicin and romidepsin have single agent activity in PTCL and CTCL. In pre-clinical studies, we demonstrated that romidepsin had synergistic effects in combination with doxorubicin. The aim of this study is to determine the safety and feasibility of the combination of romidepsin and liposomal doxorubicin in patients with relapsed/refractory CTCL and PTCL.Materials and Methods:This is a multi-center, single arm, open-label phase I dose-escalation study. Patients with relapsed/refractory CTCL (stage IIA-IV), or PTCL of any stage or subtype who received at least one systemic therapy are eligible. The primary endpoint is to identify the maximum tolerated dose (MTD) of romidepsin in combination with liposomal doxorubicin and the secondary endpoint is to determine the overall response rate (ORR) of this combination. Patients were treated with liposomal doxorubicin 20 mg/m2 on day 1 and romidepsin at four dose levels on days 1, 8 and 15, every 28 days, until 2 cycles beyond the best response, 8 cycles, disease progression (PD), or intolerability; whichever comes first. Dose levels of romidepsin include 8, 10, 12 and 14 mg/m2. Dose limiting toxicity (DLT) is defined as any adverse event during therapy including: grade 5 toxicity, any grade 4 hematologic toxicity lasting >7 days (except neutropenia), or any grade 4 non-hematologic toxicity according to CTCAE version 4.0. The MTD was defined as the highest tested dose level where two or more participants experienced a DLT utilizing a standard 3+3 design. Response was evaluated using the Cheson criteria in PTCL and patients with nodal disease and the mSWAT was utilized in CTCL. Pre-specified in the protocol, after determination of the MTD of romidepsin, up to 12 patients will be treated in a dose-expansion cohort if efficacy is noted.Results:Fourteen patients (5 PTCL, 9 CTCL) were treated at four dose-levels with a median 4 cycles (range 1-8) of therapy. Clinical data regarding these patients is included in Figure 1. Grade 3/4 non-hematologic adverse events occurred in 4 patients including 3 infection, 1 fatigue and 1 atrial fibrillation. Four patients experienced grade 3/4 hematologic toxicities: 1 neutropenia, 2 thrombocytopenia and 3 anemia. The MTD of romidepsin was determined to be 12 mg/m2 and the dose limiting toxicity was prolonged (>7 days) grade 4 thrombocytopenia. The ORR was 57%, including 2 complete responses and 6 partial responses.Given these results, three additional patients have been treated in a pre-specified dose-expansion cohort. For the 17 total patients (including 3 additional patients treated at the MTD), the ORR was 52%. In CTCL the ORR was 78% (1 CR, 6 PR, 2 PD) and among PTCL patients the ORR was 25% (1 CR, 1 PR, 1 PD).Conclusion:Here we report the results of the dose-escalation study of the combination of romidepsin and liposomal doxorubicin with preliminary data on the ORR. This combination has an acceptable toxicity profile at an MTD of 12 mg/m2 for romidepsin and has promising efficacy in both relapsed/refractory PTCL and CTCL. An additional eight patients will be included in a dose-expansion cohort. [Display omitted] DisclosuresAi:Celgene: Research Funding. Porcu:Kiowa: Research Funding; Miragen: Research Funding; Tetralogic: Research Funding; Celgene: Research Funding; Innate Pharma: Research Funding; Cell Medica: Research Funding; Galderma: Research Funding; Kura: Research Funding. Wieduwilt:Sigma-Tau: Research Funding; Reata Pharmaceuticals: Equity Ownership. Brammer:Celgene: Research Funding.

Safety and Anti-Tumour Activity of RP6530, Dual PI3K δ/γ Inhibitor, in Relapsed/Refractory T-Cell Lymphoma: Updated Results from the Dose Expansion Cohort of an on-Going Phase I/Ib Study

Introduction: RP6530 is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. Preliminary results from the ongoing Phase 1/1b T-cell lymphoma (TCL) study were presented at ASH 2016 (NCT02567656). The updated results from the escalation phase and further data on the expansion cohort treated at the maximum tolerated dose (MTD) is presented.Methods: This multicenter, open-label, Phase 1/1b study consists of dose escalation cohorts followed by two expansion cohorts enrolling 20 pts with peripheral TCL (PTCL) and 20 pts with cutaneous TCL (CTCL). The primary objective of the study is to determine the MTD and dose limiting toxicity (DLT), and to describe the safety and pharmacokinetic profiles. The secondary objectives are assessment of the overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2014) and the modified Severity Weighted Assessment Tool (mSWAT) respectively.Results: As of June 20, 2017, a total of thirty seven patients (17 PTCL and 20 CTCL) have been enrolled across the dose escalation and expansion cohorts. The results presented are the pooled data across both cohorts. Nineteen pts (9 PTCL, 10 CTCL) were enrolled in dose escalation [(200 mg BID, n=4; 400 mg BID, n=4; 800 mg BID (Fasting), n=5; 800 mg BID (Fed), n=6)] and eighteen patients (8 PTCL and 10 CTCL) in expansion (800 mg BID Fasting) in a 28 day cycle. Patients had a median of 3 (range: 1-7) and 5 (range: 1-15) prior treatment regimens for PTCL & CTCL respectively.Based on DLTs (transaminitis, rash & neutropenia), MTD was determined to be 800 mg BID fasting. A dose-proportional increase in plasma concentrations was observed in the PK. Safety assessment of 37 patients receiving at least one dose of RP6530 demonstrated an acceptable safety profile. Treatment related AE ≥Grade 3 were observed in thirteen (35%) patients which included elevated ALT/AST (n=9, 24%), rash (n=3, 8%), and neutropenia (n=1, 3%). These events were reversible and managed by withholding study drug. Steroid was given in some cases of transaminitis. There were no treatment related serious adverse events (SAE). Two patients discontinued treatment due to safety reasons. Dose reduction was done in seven patients (19%).As defined by the protocol, response assessments of the twenty evaluable patients receiving at least two cycles of RP6530 showed an ORR of 45% (9/20 patients) out of which 2 (10%) were complete responses [CR] and 7 (35%) were partial responses [PR]. Eight patients showed stable disease (40%). Indication specific analysis showed an ORR of 57% (4/7, 2 CR, 2 PR) in PTCL and 38% (5/13, 5 PR) in CTCL. Twelve patients (12/37, 32%) who discontinued treatment due to a rapid progression of disease before the first efficacy assessment were not considered for efficacy analysis.Conclusion: Based on the updated emerging data, RP6530 shows encouraging preliminary clinical activity as a single agent and appears to have an acceptable and manageable safety profile in relapsed/refractory TCL. Recruitment in the expansion cohort is currently on-going to reach a total of 40 patients and results will be further evaluated. DisclosuresRamchandren:Curis: Consultancy; Gilead Sciences: Consultancy; Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Barde:Rhizen Pharmaceuticals SA: Employment. Nair:Rhizen Pharmaceuticals SA: Employment.

Safety, pharmacokinetic and pharmacodynamic results from dose escalation of SAR439459, a TGFβ inhibitor, as monotherapy or in combination with cemiplimab in a phase 1/1b study.

2510 Background: SAR439459 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. In preclinical models, combining SAR439459 with an anti-PD-1 showed improved anti-tumor activity compared to single agent. Here we report preliminary results of SAR439459 ± cemiplimab in a first in human study. Methods: This is an open-label study (dose escalation and expansion) of SAR439459 ± cemiplimab administered intravenously in adult patients with advanced solid tumors to determine safety and tolerability, the maximum tolerated dose (MTD) and/or maximum administered dose (MAD) of SAR439459 ± cemiplimab, pharmacokinetics (PK); pharmacodynamic (PD) and preliminary clinical benefit. In Part 1A, SAR439459 (0.05-15 mg/kg) was administered as monotherapy Q2W in an adaptive Bayesian design with overdose control. In Part 1B, SAR439459 doses cleared from monotherapy were administered in combination with fixed dose of cemiplimab (3 mg/kg Q2W or 350 mg Q3W) in a 3+3 design. Results: As of 31 January 2020, 28 (1A) and 24 (1B) patients with ECOG performance status of 0-1 with a median age of 60.5 and 63 years respectively were enrolled. In Part 1A, 25 patients (89.3%) had at least one treatment emergent adverse event (TEAE) and 15 (53.5%) experienced grade (G)≥ 3 events. In Part 1B, 22 patients (91.7%) had at least one TEAE and 14 (58.3%) experienced G ≥ 3 events. Dose-limiting toxicities (DLTs) were evaluable in 24 and 21 patients respectively. In 1A, 2 DLTs were reported in 2 of 8 evaluable patients in dose level (DL) 4: G5 brain stem hemorrhage in a patient on concomitant low molecular weight heparin treatment and G3 myocardial infarction in a patient with diabetes, chronic kidney disease, chronic obstructive pulmonary disease, and hypertension. In 1B, 1 of 6 evaluable patients in DL5 had DLTs (G3 ALT and AST increase). MTD was not reached in either part. Ten patients had best overall response of stable disease: 6 in 1A and 4 in 1B. The PK of SAR439459 was dose proportional over the dose range tested with no evidence of cemiplimab effect on SAR439459 PK, when given in combination. Treatment with SAR439459 ± cemiplimab led to rapid reduction in total plasma TGFβ level in all dose levels tested and induced CD8 & NK cells expansion and Th1 cytokines production, suggesting peripheral T cell activation. Preliminary results from paired tumor biopsies collected from patients treated with SAR439459 ± cemiplimab in expansion showed trend of TGFβ signaling pathway inhibition and conversion from excluded to inflamed tumor-immune phenotype. Conclusions: SAR439459 ± cemiplimab showed an acceptable tolerability profile overall. MTD was not reached. Peripheral and tumor target engagement and modulation of key immune cells was observed in treated patients. Dose expansion cohorts are currently enrolling selected solid tumor patients. Funding: Sanofi. Clinical trial information: NCT03192345.

A phase Ib trial of alpelisib and weekly cisplatin in patients with solid tumor malignancies.

3134 Background: The PI3K pathway may represent a mechanism to overcome cisplatin resistance, particularly in human papilloma virus (HPV)-associated tumors. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies and HPV-associated tumors in the dose expansion cohort. Methods: Patients with advanced solid tumors were enrolled in this phase Ib open label study (NCT02620839). Dose escalation followed standard 3+3 design. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day cycle. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives included determining the objective response rate (ORR), median progression-free survival (PFS), and characterizing the safety profile. Results: 23 patients were enrolled in this study between September 2016-August 2018. Median age was 57 years (range 37-83), and 57% of patients were female. Tumor sites included prostate (22%), cervical (13%), endometrial (13%), breast (9%), anal (9%), penile (9%), and other (26%). 91% of patients had > 3 lines of prior therapy, with 74% who previously received a platinum. Median duration of treatment was 8.7 weeks (range 1-57.5). The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. 9 patients discontinued the study during cycle 1 due to an adverse event without progression. There were 3 DLTs, all of which were grade 4 hyperglycemia: 2 at alpelisib 250 mg and 1 at alpelisib 300 mg. Treatment-related grade 3-4 toxicities included hyperglycemia (13%), rash (13%), neutropenia (9%), anemia (4%), thrombocytopenia (4%), neuropathy (4%), and diarrhea (4%). Any grade nephropathy occurred in 17%. Dose reductions and/or interruptions were required in 61% of patients. There was a significant decrease in administered cisplatin dose intensity (33.8%) with a planned weekly cisplatin dose of 35 mg/m2 and alpelisib 250 mg. In contrast, dose intensity ranged from 55-85% for other dose levels with an intended cisplatin dose of 30 mg/m2. Dose expansion was not conducted due to significant early and cumulative toxicity. Of the 14 patients with post-baseline assessment available, ORR was 29%, with all 4 patients demonstrating partial response and 7 patients (50%) with stable disease. Of the 4 responders, tumor sites included 2 endometrial cancers, cervical neuroendocrine carcinoma, and penile SCC, and 3 were platinum-refractory. Median PFS measured 3.1 months (95% CI 1.3-4.1). 5 of 21 patients had PIK3CA mutations, with no difference in PFS ( p= 0.76). Conclusions: While alpelisib and cisplatin demonstrated responses among patients with solid tumor malignancies, the combined adverse event profile presented significant dose intensity limitations. Future prospective studies are planned using carboplatin and alpelisib to improve the toxicity and tolerability. Clinical trial information: NCT02620839.