Incidence Of Dose-limiting Toxicities Research Articles

A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

PB1849: TRIAL IN PROGRESS: PHASE IB/II STUDY OF SIREMADLIN IN COMBINATION WITH VENETOCLAX + AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY

Background: Treatment options for patients with AML who are not candidates for intensive chemotherapy (IC) are limited. The addition of venetoclax to hypomethylating agents demonstrated improved remission rates and survival; however, relapse rates are high, and most patients remain measurable residual disease (MRD) positive (DiNardo CD, N Engl J Med, 2020). Murine double minute-2 (MDM2) is a key negative regulator of tumor protein 53 (p53). Inhibition of the p53-MDM2 interaction results in up-regulation of the tumor-suppressive effect of p53. Siremadlin is a selective inhibitor of the p53-MDM2 interaction. Siremadlin + venetoclax has shown durable antitumor responses in p53-wild-type AML patient-derived xenograft models (Wang Y, Cancer Res, 2019). Findings from a first-in-human Phase I study with siremadlin demonstrated a tolerable safety profile and preliminary antitumor activity in patients with AML (Stein EM, Clin Cancer Res, 2021; NCT02143635). Preliminary results from the ongoing Phase Ib study exploring siremadlin in combination with venetoclax showed promising antileukemic activity in patients with relapsed/refractory AML (Wei AH, ASH 2021; NCT03940352). Aims: Here we describe the study design of a Phase Ib/II study to assess the safety and efficacy of the novel combination of siremadlin + venetoclax + azacitidine in patients with AML who are unfit for IC (NCT05155709). Methods: The study will enroll approximately 55 adult patients with AML who are unfit for IC due to older age (≥75 y) or presence of comorbidities (cardiac or pulmonary, Eastern Cooperative Oncology Group performance status of 2 or 3). Patients with prior myelodysplastic syndrome, myelofibrosis, essential thrombocythemia, polycythemia, or therapy-related AML may also be eligible. Patients with TP53 mutation or del17p are excluded. Two subpopulations will be evaluated in 2 arms: patients with prior suboptimal response (no complete remission [CR], CR with partial/incomplete hematologic recovery [CRh/CRi], or morphologic leukemia-free state) after 2-4 cycles of first-line venetoclax + azacitidine (Arm 1) and patients with newly diagnosed AML with high-risk clinical features that confer a low likelihood of response to venetoclax + hypomethylating agents (adverse genetic risk stratification per European Leukemia Network, 2017; Arm 2). The study will consist of a safety run-in (Part 1) and expansion phase (Part 2; Figure). The safety run-in will evaluate safety across 2 siremadlin dose levels (20 or 30 mg) from Day (D)1 to D5 in each 28-d treatment cycle in combination with venetoclax and azacitidine. In Arm 1, pts will continue receiving their venetoclax and azacitidine doses that were evaluated as tolerable prior to study enrollment. In Arm 2, venetoclax will be ramped up over 3 days to a target daily dose of 400 mg and azacitidine (75 mg/m2) will be administered from D1–D7 or from D1–D5, and D8 and D9). Upon confirmation of the recommended dose for expansion (RDE, determined for each arm separately), enrollment for the expansion phase (Part 2) will open; patients will be treated with siremadlin at the RDE in combination with venetoclax + azacitidine. The primary endpoints are incidence of dose-limiting toxicities (Arm 1 and Arm 2 separately) and CR rate (Arm 1 only). Secondary endpoints include safety and tolerability; CR rate (Arm 2 only); CR/CRh and CR/CRi rates; duration of CR, CRi, and CRh; overall survival; early mortality; MRD; and pharmacokinetics. Results: None, trial in progress. Image:Summary/Conclusion: None, trial in progress.

PB2012: A PHASE 2 MULTIARM STUDY OF MAGROLIMAB COMBINATIONS IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA

Background: Magrolimab is a first-in-class humanized monoclonal antibody that blocks the immune checkpoint CD47, a “do not eat me” signal, overexpressed on tumor cells. Binding of magrolimab to CD47 leads to phagocytosis of cancer cells in human solid tumors and hematologic malignancies. CD47 is highly expressed in multiple myeloma (MM), and overexpression contributes to MM pathogenesis. Blocking of CD47 induces immediate activation of macrophages and elimination of myeloma cells. Hence, a blockade of CD47 with magrolimab may have therapeutic benefit in patients with MM. Additionally, in vitro studies have shown synergy between magrolimab and daratumumab in MM cell line phagocytosis, and complimentary mechanisms suggest potential enhanced efficacy in other combinations. Aims: To evaluate the safety, tolerability, and efficacy of magrolimab in combination with commonly used myeloma therapies in patients with relapsed/refractory MM (RRMM). Methods: This phase 2 open-label multiarm study includes patients aged ≥18 years currently requiring treatment for RRMM; all participants must have received ≥3 previous lines of therapy for MM, including an immunomodulatory drug and a proteasome inhibitor. This study includes safety run-in and corresponding dose-expansion phases with the following combinations: magrolimab + daratumumab, magrolimab + pomalidomide + dexamethasone, magrolimab + carfilzomib + dexamethasone, and magrolimab + bortezomib + dexamethasone (Figure). Magrolimab + bortezomib + dexamethasone may be initiated based on the preliminary safety and efficacy of magrolimab + carfilzomib + dexamethasone, and, if initiated, only requires 1 prior line of therapy. The primary objectives of the safety run-in phase are to evaluate the safety and tolerability of magrolimab and determine the recommended phase 2 dose (RP2D), with incidence of dose-limiting toxicities (DLTs), adverse events, and laboratory abnormalities as the primary endpoint. The dose-expansion phase will evaluate efficacy, with objective response rate as the primary endpoint. Secondary endpoints include duration of response, progression-free survival, and overall survival. Minimal residual disease negativity, biomarker changes from baseline, immune cell signaling alterations, and the mutational profile of myeloma cells will also be explored. Magrolimab will be administered intravenously as an initial priming dose to mitigate on-target anemia, followed by a maintenance dose on days 8, 15, 22, and 29 during cycle 1 (35 days); days 1, 8, 15, and 22 during cycle 2 (28 days); and days 1 and 15 from cycle 3 (28 days) onward (maximum of 8 cycles in patients who previously received bortezomib). Daratumumab, pomalidomide, dexamethasone, carfilzomib, and bortezomib will be administered according to manufacturer’s prescribing information. Dose de-escalation may occur based on DLTs per protocol in the safety run-in cohorts; magrolimab doses will not be reduced in the dose-expansion cohorts. Patients will continue treatment until unacceptable toxicity, progressive disease, or patient/investigator choice to discontinue. Planned enrollment is approximately 153 patients, with up to 27 in each safety run-in cohort and 72 in the dose-expansion cohorts following completion of the safety run-ins. Results: Trial in progress. Image:Summary/Conclusion: Patient recruitment is ongoing. Clinical trial information: NCT04892446.

Abstract CT529: A Phase 1b Study of CG0070 combined with nivolumab in cisplatin ineligible patients with muscle invasive bladder cancer

Abstract Background: Up to 50% of patients with muscle invasive bladder cancer (MIBC) are unable to receive neoadjuvant chemotherapy, creating an unmet clinical need for alternative systemic treatment. Results from recent neoadjuvant immune checkpoint blockade (ICB) studies signal pCR rates between 31-42%. However, there was a clear dichotomy in response between patients with high vs. low pre-treatment lymphocytic infiltration. In tumors exhibiting immune excluded or immune desert phenotypes, therapeutic strategies to attract CD8+ T cells infiltration prior to ICB may be beneficial. CG0070 is an oncolytic adenovirus designed to preferentially replicate through a transcriptionally regulated promoter that is up-regulated in RB-pathway-defective cells (>70% of MIBC). In addition, CG0070 expresses GM-CSF to attract antigen presenting cells to the tumor microenvironment. We hypothesize that combination therapy using intravesical CG0070 and systemic Nivolumab is 1) safe and 2) can enhance local and systemic treatment response in the neoadjuvant setting against MIBC. Methods: This is a phase Ib trial evaluating 2 doses of nivolumab (4 weeks apart) with 6 weekly intravesical CG0070 followed by cystectomy. Dose-limiting toxicities (DLTs) will be assessed in 6 DLT-evaluable patients in a safety lead-in phase. The combination would be declared tolerable if the incidence of DLTs is <33%, and the study expanded to 30 patients. Key eligibility: cT2-T4aN0-1M0 stage, no autoimmume disease within 2 years, and no concurrent invasive upper tract carcinoma or other active cancer. The primary objective is to evaluate the safety of combination therapy according to CTCAE v5.0. The secondary objective is to assess the changes in the lymphocytic infiltration following combination therapy and to assess the antitumor efficacy of combination therapy. Exploratory endpoints include assessing the predictive value of E2F expression, tumor mutational burden, immune infiltration, and various peripheral blood for treatment response. Study Progress: Study is actively accruing. Clinical trial information: NCT04610671. An update on the study will be provided at the time of presentation. Citation Format: Roger Li, Wade Sexton, Phillipe Spiess, Scott Gilbert, Julio Pow-Sang, Jingsong Zhang, Gustavo Borjas, Paola Grandi, James Burke, Rohit Jain, Jose Conejo-Garcia. A Phase 1b Study of CG0070 combined with nivolumab in cisplatin ineligible patients with muscle invasive bladder cancer [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 CT529.

Abstract CT519: FCN-159, a MEK1/2 inhibitor, in patients with advanced melanoma harboring NRAS mutations: A phase 1A dose-escalation study

Abstract Purpose: No targeted therapy has been approved for NRAS-mutant melanoma. We evaluated the safety and tolerability and determined the recommended phase 2 dose (RP2D) of FCN-159, a selective MEK1/2 inhibitor, in patients with NRAS-mutant advanced melanoma. Methods: This single-arm, open-label, dose-escalation, phase 1A study in China (NCT03932253) enrolled patients with unresectable stage III/IV melanoma harboring NRAS mutations. Patients received FCN-159 in doses escalating from 0.2 mg until the maximum tolerated dose (MTD). Oral FCN-159 was given once in the single-dose period and once daily (QD) in 28-day cycles in the continuous-dose period. The primary endpoint was the incidence of dose-limiting toxicity (DLT). Results: As of September 16, 2021, 33 patients were enrolled and received 0.2-15 mg FCN-159. All patients had received systemic treatments. One DLT event (grade 3 folliculitis) occurred in the 15 mg group, and no DLT occurred at other dose levels; MTD was defined as 15 mg QD. Grade ≥3 treatment-emergent adverse events (TEAEs) deemed related to FCN-159 were reported in 5 (15.2%) patients across dose levels; stomatitis (2; 6.1%) was the most common. No FCN-159-related TEAEs were serious or led to treatment discontinuation. Among 21 patients assigned to doses ≥6 mg, 4 had investigator-confirmed objective responses (objective response rate, 19.0%; 95% confidence interval [CI], 5.4-41.9); all were partial responses (Table). Median DOR was 4.8 months (95% CI, 2.8-NE). Seven patients had SD (CBR, 52.4%; 95% CI, 29.8-74.3). Median progression-free survival was 3.8 months (95% CI, 1.8-5.6). FCN-159 12 mg QD was determined to be the RP2D per assessment of safety, antitumor activity, and pharmacokinetic data. Conclusion: FCN-159 was well tolerated and showed antitumor activity in patients with NRAS-mutant advanced melanoma. FCN-159 12 mg QD as a treatment for NRAS-mutant advanced melanoma warrants future investigation. Tumor response was assessed by the investigators according to Response Evaluation Criteria in Solid Tumors version 1.1.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; DOR, duration of response; NA, not applicable; NE, not evaluable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Table. Confirmed best overall response 6 mg(n = 5) 8 mg(n = 4) 12 mg(n = 6) 15 mg(n = 6) Total(N = 21) Confirmed BOR, n (%) CR 0 0 0 0 0 PR 2 (40.0) 1 (25.0) 0 1 (16.7) 4 (19.0) SD 1 (20.0) 1 (25.0) 3 (50.0) 2 (33.3) 7 (33.3) PD 2 (40.0) 2 (50.0) 1 (16.7) 2 (33.3) 7 (33.3) NE 0 0 2 (33.3) 1 (16.7) 3 (14.3) ORR, n (%), 95% CI 2 (40.0), 5.3–85.3 1 (25.0), 0.6–80.6 0 1 (16.7), 0.4–64.1 4 (19.0), 5.4–41.9 CBR, n (%), 95% CI 3 (60.0), 14.7–94.7 2 (50.0), 6.8–93.2 3 (50.0), 11.8–88.2 3 (50.0), 11.8–88.2 11 (52.4), 29.8–74.3 Median DOR (95% CI), months 4.8 (2.8–NE) NR (NE–NE) NA NR (NE–NE) 4.8 (2.8–NE) Citation Format: Lili Mao, Jun Guo, Lingjun Zhu, Yu Jiang, Wangjun Yan, Jian Zhang, Ai-min Hui, Zhuli Wu, Yuchen Yang, Han Zhao, Yiqian Jiang, Lu Si. FCN-159, a MEK1/2 inhibitor, in patients with advanced melanoma harboring NRAS mutations: A phase 1A dose-escalation study [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 CT519.

Abstract CT218: First-in-human trial of intravenous MEDI9253, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors

Abstract Background: Oncolytic viruses selectively infect tumors and activate antitumor immune responses via innate and adaptive pathways, leading to immunogenic cell death and potentiating the efficacy of immune checkpoint inhibitors. MEDI9253 is a recombinant Newcastle disease virus (NDV) that incorporates a human transgene encoding the immunostimulatory cytokine interleukin (IL)-12, which leads to tumor cell lysis and localized IL-12 expression. Preclinical studies show that MEDI9253 induces PD-L1 expression and recruits innate and adaptive immune cells to the tumor microenvironment (TME) and indicate that its antitumor activity is enhanced by concurrent PD-L1 blockade. This clinical study is evaluating intravenous (IV) MEDI9253 in combination with the anti-PD-L1 antibody durvalumab in patients with selected advanced solid tumors. Methods: This is a phase I, multicenter, open-label, dose escalation and dose expansion trial (NCT04613492) enrolling patients with microsatellite-stable colorectal cancer (MSS-CRC), renal cell carcinoma (RCC) or melanoma. Eligibility criteria include progressed/refractory disease or intolerance to all prior lines of therapy with proven survival benefit for recurrent/metastatic disease. Patients must have life expectancy ≥12 weeks by GRIm score; histologically documented disease; adequate performance status (ECOG 0-1); adequate organ function; and presence of RECIST v1.1 measurable disease amenable to repeated biopsy. Exclusion criteria include untreated/uncontrolled metastatic CNS involvement. Patients must take precautions to prevent the theoretical risk of NDV transmission to humans and birds. The trial will enroll up to ~192 patients across 30 centers globally. The dose escalation phase will evaluate a single dose of IV MEDI9253 with sequential IV durvalumab, then multiple-dose cohorts of up to 4 ascending dose levels of MEDI9253 with sequential or concurrent durvalumab. The dose expansion phase will include 3 cohorts of ~20 patients, each enrolling a single tumor type. In both phases, durvalumab will be dosed for up to 2 years or until disease progression, clinical deterioration, withdrawal of consent or unacceptable toxicity. Pretreatment and on-treatment tumor biopsies are required for patients in multiple-dose cohorts. The primary objectives are evaluating the safety, tolerability and incidence of dose-limiting toxicities of MEDI9253 and identifying the optimal dose/schedule in combination with durvalumab. Secondary objectives include assessing initial efficacy (response and progression-free survival by RECIST v1.1, and overall survival), pharmacodynamics in the TME, immunogenicity, and pharmacokinetics (viremia and IL-12). The trial is recruiting. Citation Format: Noelia Purroy, Nicholas Durham, Marc Phillips, Maureen M. Hattersley, Lindsey Jung, Diwakar Davar, Dmitriy Zamarin, Tanner M. Johanns, Igor Puzanov. First-in-human trial of intravenous MEDI9253, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors [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 CT218.

Combination of nivolumab with chemoradiotherapy for locally advanced cervical cancer: NiCOL phase I trial.

5534 Background: Current management of locally-advanced cervical cancers (LACC) relies on chemoradiotherapy (CRT) and brachytherapy. The causal relation between cervical cancer and human papillomavirus infection, which engenders tumor expression of immunoreactive neo-antigens, together with high PD-L1 expression, warrants consideration of immune checkpoint inhibitors (ICI) in the definitive treatment of this disease. We assessed the safety of concurrent and maintenance nivolumab in addition to CRT in patients with LACC. Methods: This prospective, multi-center, dose-confirmation, phase I clinical trial (NiCOL trial; NCT03298893) evaluated the tolerance profile of concurrent and maintenance nivolumab in addition to CRT (45 Gy in 25 fractions with cisplatin 40mg/m² q1w, followed by a brachytherapy boost to 85 Gy) for stage IB3-IVA cervical cancers. Nivolumab was administered at 240 mg q2w starting on day 1 of CRT and in maintenance after CRT completion for up to 6 months (13 cycles). The primary endpoint was the incidence of dose-limiting toxicities (DLT) within 11 weeks after the initiation of treatment (defining the DLT assessment period), corresponding to the first 6 cycles of nivolumab. DLT were defined as grade ≥3 non-hematological toxicities, grade ≥3 immune-related adverse event (irAE), persistent grade ≥2 irAE for ≥1 week despite optimal supportive care, or ≥1-week radiotherapy delay related to treatment toxicity. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and treatment tolerance profile. Results: 16 patients (pts) were recruited between 11/2017 and 07/2020. Median age was 46 years [range: 27-77]. Histological types were squamous cell carcinomas (n = 14) and adenocarcinomas (n = 2). Tumors were staged as FIGO IB3 (n = 2), IIB (n = 8), IIIB (n = 1), IIIC1 (n = 4) and IVA (n = 1); 13 tumors were HPV-positive. Three patients experienced DLT, corresponding to grade 3 hypotension (n = 2) and grade 3 acute kidney injury (n = 1). Following the DLT assessment period, while receiving maintenance nivolumab, one patient developed a grade ≥3 irAE corresponding to a grade 3 diarrhea. Two months after brachytherapy completion, ORR was 93.8% [95%CI: 69.8%-99.8%]. With a median follow-up of 16.6 months, three patients experienced disease control failure (at 3,4 and 5 months); site of disease progression was local for two patients, and simultaneously local and distant for one patient. One-year PFS was 81.2% [95% CI: 64.2%-100%]. Conclusions: Concomitant nivolumab with definitive CRT, followed by maintenance nivolumab, appears to be a safe and feasible therapeutic option for LACC, associated with encouraging PFS rates. Further trials evaluating ICI combined with CRT for LACC are warranted in light of these promising results and of those from recent studies evaluating ICI in the metastatic setting. Clinical trial information: NCT03298893.

A phase Ia/Ib study of talazoparib in combination with tazemetostat in metastatic castration-resistant prostate cancer (mCRPC).

TPS5098 Background: Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in metastatic castration-resistant prostate cancer (mCRPC), and is linked to lineage plasticity and therapy resistance. In pre-clinical studies, EZH2 directly regulates DNA damage repair (DDR) gene expression, and pharmacologic inhibition of EZH2 sensitizes prostate cancer cells to genotoxic stress as induced by poly-ADP ribose polymerase (PARP) inhibition. The PARP inhibitor talazoparib and EZH2 inhibitor tazemetostat are currently under study in mCRPC, and we are conducting a Phase 1 clinical trial of the combination. Methods: Phase 1a of the study will define the recommended phase 2 dose (RP2D) and Phase 1b will better assess safety and preliminary clinical activity of the combination at the RP2D. Eligible patients must have progressive disease after at least one secondary hormonal therapy and taxane-based chemotherapy (or felt not to be more appropriate for taxane), have disease evaluable for response (PSA ≥ 2 ng/ml or measurable disease by RECIST 1.1) and have a metastatic lesion amenable to biopsy adequate for next generation sequencing. In Phase 1a (n = 9-18), the starting doses are talazoparib 0.75 mg daily and tazemetostat 600 mg BID, with dose escalation/de-escalation of both agents by up to 2 dose levels [DLs] based on a 3+3 design. The RP2D is the maximum tolerated dose (MTD) or DL +2 (talazoparib 1 mg daily + tazemetostat 800 mg BID) if the MTD is not reached. After 6 patients are treated at the RP2D, phase 1b will enroll an additional 20 patients to an expansion cohort. The primary endpoint of safety and tolerability is based on incidence of dose-limiting toxicities [DLTs] and incidence and grade of adverse events [AEs] by CTCAE version 5.0. For the secondary endpoint of overall response rate (ORR; defined as PSA reduction by ≥ 50% OR radiographic response by RECIST 1.1), with a sample size of 26 (6 patients from dose escalation and 20 from expansion), we deem talazoparib+tazemetostat effective if ORR is ≥ 5/26 (19%). The probability of concluding that the treatment strategy effective is 0.11 if its true response rate is 10% and at least 0.93 if the true response rate exceeds 30%. Mandatory pre-treatment and on-treatment (8-week) biopsies will undergo targeted genetic sequencing, transcriptomic profiling, ChIP (Chromatin ImmunoPrecipitation)-seq, and immunohistochemistry (IHC) for DDR and differentiation markers; blood specimens will undergo circulating cell-free DNA and circulating tumor cell profiling – these studies will nominate possible predictive biomarkers for therapeutic response and serve as pharmacodynamic markers of combined PARP and EZH2 inhibition. The goal of this study is to expand treatment options in mCRPC through a novel approach to exploit EZH2 as a therapeutic target through co-targeting the DDR response. Enrollment began in July 2021. Clinical trial information: NCT04846478.

ARV-471, an estrogen receptor (ER) PROTACdegrader, combined with palbociclib in advanced ER+/human epidermal growth factor receptor 2–negative (HER2-) breast cancer: Phase 1b cohort (part C) of a phase 1/2 study.

TPS1120 Background: ARV-471 is a novel, potent, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader that selectively targets the ER. In xenograft models, ARV-471 demonstrated substantially greater ER degradation and antitumor activity compared with the selective ER degrader fulvestrant. In the phase 1 dose escalation portion (Part A) of the first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed antitumor activity in patients with ER+/HER2- locally advanced or metastatic breast cancer who had previously received endocrine therapy and a cyclin-dependent kinase (CDK)4/6 inhibitor; the clinical benefit rate (rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26%–56%) in 47 evaluable patients. The phase 2 VERITAC expansion cohort (Part B) is further evaluating ARV-471 monotherapy in this patient population. Palbociclib, a CDK4/6 inhibitor, plus fulvestrant is a standard treatment option for patients with ER+/HER2- breast cancer who have had disease progression on endocrine therapy. ARV-471 plus palbociclib resulted in substantially greater tumor growth inhibition in xenograft models compared with palbociclib plus fulvestrant, supporting further investigation of the ARV-471 plus palbociclib combination in patients with ER+ breast cancer. Here we describe Part C of the phase 1/2 study, which evaluates the safety and clinical activity of ARV-471 plus palbociclib in patients with breast cancer who previously received endocrine therapy. Methods: Eligible patients (aged ≥18 years) have histologically or cytologically confirmed ER+/HER2- advanced breast cancer and have received ≥1 prior endocrine therapy and ≤2 prior chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor therapy is permitted. Patients with known symptomatic brain metastases requiring steroids are excluded. ARV-471 and palbociclib will be administered orally once daily in 28-day cycles; ARV-471 will be given continuously and palbociclib for 21 days followed by 7 days off treatment. Primary objectives are to evaluate the safety and tolerability of ARV-471 plus palbociclib and select the recommended phase 2 dose and schedule of the combination (based on the incidence of dose-limiting toxicities during the first cycle and the frequency and severity of adverse events and laboratory abnormalities). Secondary objectives are to assess preliminary antitumor activity of ARV-471 plus palbociclib (based on overall response rate per Response Evaluation Criteria in Solid Tumors v1.1, clinical benefit rate, progression-free survival, and duration of response) and pharmacokinetic parameters. Clinical trial information: NCT04072952.

EVOKE-02: A phase 2 study of sacituzumab govitecan (SG) plus pembrolizumab (pembro) with or without platinum chemotherapy in first-line metastatic non–small cell lung cancer (NSCLC).

TPS9146 Background: Most patients (pts) with advanced NSCLC do not harbor genomic alterations associated with approved first-line targeted therapies. The standard of care for these pts is a programmed death (ligand)-1 (PD-[L]1) inhibitor alone, if the tumor highly expresses PD-L1, or in combination with platinum doublet chemotherapy, independent of PD-L1 expression. However, most pts do not respond to these therapies or achieve only a transient response, highlighting an unmet need. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. In the phase 1/2 IMMU-132-01 basket study (NCT01631552), SG demonstrated an objective response rate (ORR) of 17% and median overall survival (OS) of 9.5 mo, with a manageable safety profile in 54 pts with metastatic NSCLC after multiple prior therapies (Heist RS, et al. J Clin Oncol. 2017). We hypothesize that combining SG with pembro or with pembro + platinum chemotherapy will improve outcomes for pts with advanced NSCLC. Methods: EVOKE-02 (NCT05186974) is an open-label, multicenter, multicohort, global phase 2 study evaluating SG plus pembro with or without carboplatin (carbo) or cisplatin (cis) in advanced NSCLC. Key eligibility criteria include age ≥18 y, stage IV NSCLC at enrollment, measurable disease by RECIST v1.1, ECOG performance status of 0 or 1, and adequate organ function. Pts must not have actionable genomic alterations and must not have received prior systemic therapy for metastatic NSCLC. Up to 164 pts will be enrolled. SG plus pembro will be assessed in squamous/nonsquamous NSCLC with Tumor Proportion Score (TPS) ≥50% (cohort A, ̃30 pts) and TPS < 50% (cohort B, ̃30 pts), and SG plus pembro with carbo/cis in nonsquamous (cohort C, ̃40 pts) and squamous (cohort D, ̃40 pts) NSCLC regardless of PD-L1 expression. Pts are randomly assigned if cohorts enrolling concurrently have overlapping eligibility. SG will be administered intravenously (IV) at 10 mg/kg on d 1 and 8 until disease progression or unacceptable toxicity, pembro 200 mg IV on d 1 for up to 35 cycles, carbo AUC 5 or cis 75 mg/m2 on d 1 for up to 4 cycles in 21-d cycles. A safety run-in will be conducted for cohorts C and D (up to 24 pts each) to determine the optimal SG dose by dose de-escalation. Choice of platinum will be based on preliminary efficacy in safety run-in. The primary endpoints are ORR assessed by independent review per RECIST v1.1 and the incidence of dose-limiting toxicities per dose for the first 21 d of the safety run-in to determine the recommended phase 2 dose of SG in combination with pembro and a platinum. Key secondary endpoints include progression-free survival by independent review, OS, duration of response, disease control rate, and safety. This study is open for recruitment and is enrolling globally. Clinical trial information: NCT05186974.

Initial efficacy and biomarker analysis of a phase 1b study targeting IL-1β and PD-1 with chemotherapy in metastatic pancreatic cancer (PanCAN-SR1).

e16287 Background: Pancreatic ductal adenocarcinoma (PDA) has been refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1β was upregulated in PDA tumors, and in mouse models, IL-1β expression led to activation of pancreatic stellate cells and immunosuppression. We hypothesize that blockade of IL-1β and PD-1 will result in significant alterations in immune and fibroblast subsets within the PDA microenvironment. Methods: We conducted an open-label multicenter Phase Ib study evaluating gemcitabine and nab-paclitaxel with canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) mAb, and spartalizumab (PDR001), a mAb directed against human PD-1. 10 subjects with untreated metastatic PDA and RECIST measurable disease were enrolled. The primary objective was to identify a recommended phase II/III dose by evaluating the incidence of DLTs in the first 56 days. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability and preliminary assessment of clinical activity. Results: 10 subjects were enrolled between November 2020 and March 2021. 6 out of 10 were evaluable for the dose confirmation. In the dose confirmation analysis there were no dose limiting toxicities (DLTs) and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) and nab-paclitaxel (125 mg/m2 IV) on day 1,8,15; canakinumab (250 mg via subcutaneous injection) and spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. A preliminary efficacy analysis confirms 1 PR and 7 pts with SD. Two of the 7 pts have been treated for 11 and 12 cycles, respectively, without progression. Activation of CD8 T cells in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 were observed in patient samples. Using an in vitro suppression assay, we showed that baseline serum, from patients deriving clinical benefit, could induce myeloid derived suppressor cells, but that this effect was abrogated with treatment. Single cell transcriptional profiling also revealed treatment-dependent shifts in T cell activation state and myeloid cells in the tumors of patients experiencing clinical benefit. Conclusions: In this Phase Ib study, we established the Phase II/III dose of canakinumab and spartalizumab with chemotherapy in first line metastatic PDA. Translational studies suggest putative biomarkers that may help identify responding pts. This novel combination is being evaluated in a randomized Phase II/III study through the Precision Promise clinical trial network. Clinical trial information: NCT04581343.

First-in-human, phase 1, open-label, dose-escalation, dose-expansion study of ADCT-901 as monotherapy in patients with select advanced solid tumors.

TPS3157 Background: Kidney associated antigen 1 (KAAG1) is highly and selectively expressed on tumor cell surface, such as ovarian, prostate, and triple negative breast cancers (TNBC), and is rapidly internalized and co-localized with a lysosomal marker, making an ideal candidate for an antibody-drug conjugate (ADC) target. ADCT-901 is an ADC composed of a humanized monoclonal antibody IgG1 against KAAG1, conjugated through a cathepsin-cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In mouse xenograft models of human-derived TNBC, ovarian, and renal cancers significant tumor reduction was observed after a single dose of ADCT-901, providing the rationale for clinical development of a PBD-based ADC to treat KAAG1 expressing tumors (Zammarchi et al, AACR 2019). This study aims to identify the recommended dose and schedule for expansion and to characterize safety and tolerability of ADCT-901 in patients (pts) with selected advanced solid tumors that generally express KAAG1. Methods: ADCT-901-101 is a phase 1, multicenter, 2-part, open-label study that will enroll ̃70 pts (NCT04972981). Part 1: pts will receive escalating doses of ADCT-901 guided by a 3+3 design (1st dose: 15 µg/kg every 3 weeks [Q3W]; highest dose: 290 µg/kg Q3W). Dose escalation will be evaluated by administering the lowest dose to first 3 pts, then increasing/decreasing the dose based on dose-limiting toxicity (DLT) experienced by pts. The dose and schedule of ADCT-901 identified in part 1 will be tested in part 2 to characterize safety, tolerability, and preliminary efficacy of ADCT-901. Primary endpoints include incidence of DLTs (part 1 only), frequency/severity of adverse events (AE) and serious AE, clinically significant changes in vitals, laboratory values, overall tolerability, and frequency of dose interruptions and reductions. Secondary endpoints include overall response rate, duration of response, progression-free and overall survival, pharmacokinetic parameters of ADCT-901 total antibody, PBD-conjugated antibody, unconjugated SG3199 in serum, and frequency of confirmed positive antidrug antibody responses. Exploratory endpoints include tumor modulation and potential pharmacodynamic changes. Key inclusion criteria: pathologic diagnosis of selected solid tumor (cholangiocarcinoma, renal cell carcinoma, ovarian/fallopian tube and prostate cancers, TNBC) locally advanced or metastatic at time of screening, pts refractory or intolerant to existing therapy, tissue biopsy or available tissue sample, ECOG of 0-2, and adequate organ function based on predefined laboratory parameters. Pts with symptomatic CNS metastases and clinically significant third space fluid accumulation will be excluded. The study opened for recruitment in September 2021; enrollment is ongoing. Funding: ADC Therapeutics; medical writing: CiTRUS Health Group. Clinical trial information: NCT04972981.

Surv-CRM-12: A Bayesian Phase I/II Survival CRM for right-censored toxicity endpoints with competing disease progression

The growing interest in new classes of anti-cancer agents, such as molecularly-targeted therapies (MTAs) and immunotherapies with modes of action different from those of cytotoxic chemotherapies, has changed the dose-finding paradigm. In this setting, the observation of late-onset toxicity endpoints could likely be precluded by trial discontinuation due to disease progression, defining a competing event to toxicity. Trial designs where dose-finding is modeled in the framework of a survival competing risks model appear particularly suited. We aimed to provide a phase I/II dose-finding design that allows the dose-limiting toxicity (DLT) outcomes to be delayed or unobserved due to competing progression within the possibly long observation window. The proposed design named the Survival-12-continual reassessment method (Surv-CRM-12), based on survival models for right-censored DLT and progression endpoints, aimed at identifying a dose that optimized the progression outcome among a set of acceptable doses. In this competing risks framework, cause-specific hazards for DLT and progression-free of DLT were considered, with model parameters estimated using Bayesian inference. The optimal dose is that dose level that minimizes the cumulative incidence of progression among an acceptable set of doses with a cumulative incidence of DLT below a target threshold. In a simulation study, design operating characteristics were evaluated and compared to the TITE-BOIN-ET design and a nonparametric benchmark approach. The performances of the proposed method were consistent with the complexity of scenarios as assessed by the nonparametric benchmark. We found that the proposed design presents desirable operating characteristics in selecting the optimal dose and safety. We propose a design for phase I/II trials targeting the subdistribution function of toxicity and progression for dose-finding, using working models for censored data. It allows prolonged observation windows resulting in administrative censoring and competing risks. Dose-finding; Phase I/II; Competing risks; Survival data; Oncology Les auteurs n'ont pas précisé leurs éventuels liens d'intérêts.

Phase 1/2 trial evaluating the effectiveness and safety of dose-adapted Hypofractionated pelvic radiotherapy for Advanced Cervical cancers INeligible for ChemoTherapy (HYACINCT)

Background The standard treatment for locally advanced cervical cancer (LACC) is concurrent chemoradiation (CRT) followed by brachytherapy (BRT). The addition of chemotherapy (ChT) to radiotherapy (RT) is associated with a 7.5% improvement in overall survival but with more grade 3–4 acute toxicities (16.4% vs 4.9%, CRT vs RT alone). The risk-benefit ratio could be less favorable in advanced disease with renal dysfunction secondary to tumor-related hydronephrosis; borderline cardiac function; and frail patients. RT alone followed by BRT achieves long-term locoregional control <62%. Hypofractionated RT (HF-RT) using older techniques result in comparable disease control and low late toxicity rates (4–8%). Dose-adapted HF-RT using intensity-modulated RT with nodal simultaneous integrated boost (nSIB) could improve tumor control and toxicity, when ChT is contraindicated. Methods The HYACINCT study is a two-phase study to determine the effectiveness and safety of HF-RT with nSIB in LACC when ChT is contraindicated. Phase 1 is a dose-escalation study using standard 3 + 3 design, to determine the maximum tolerated dose (MTD) for nSIB in combination with pelvic HF-RT (2.67 Gy x 15 fractions). Phase 2 is a single-arm clinical trial using Simon’s two-stage design, to assess the efficacy of HF-RT with nSIB in terms of tumor response. Adult women with biopsy-proven, untreated LACC, with contraindication to ChT will be included in this trial. Discussion For the phase 1, the primary endpoint is dose-limiting toxicity (DLT), or any grade ?3 acute or sub-acute toxicity. The dose level at which incidence of DLT is ?33% is defined as the maximum tolerance dose (MTD). For the phase 2, the primary endpoint is complete response at 3 months post-treatment. Secondary outcomes are progression-free and overall survival, acute and late toxicity, and patient-reported outcomes (EPIC, EORTCQLQ C30 + CX24, PGIC, PCIS). Trial registration: NCT05210270

A phase II trial of abemaciclib (abema) and atezolizumab (atezo) in unselected and CDK12-loss metastatic castration-resistant prostate cancer (mCRPC).

TPS213 Background: Alterations in the cell cycle signaling pathway are common in mCRPC and may contribute to resistance to AR-targeted therapies. Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) have revolutionized the therapeutic landscape in ER+ breast cancer and have demonstrated robust anti-tumor activity in multiple pre-clinical mCRPC models such as enzalutamide-resistant cell lines, including those with the androgen-receptor splice variant 7 (AR-V7). Pre-clinical synergy has also been seen in multiple studies of CDK4/6i and anti-programmed death 1 (PD-1) or PD-ligand-1 (PD-L1). Additionally, loss of function alterations of CDK12, found in 5-7% of mCRPC, may confer vulnerability to anti-PD-L1 agents. Methods: This multi-center study will enroll 54 unselected mCRPC patients (pts), randomized 1:1 to abema (arm A) or abema + atezo (arm B); and 21 pts with known loss of function mutations in CDK12 (arm C) treated with atezo (n = 5) or abema + atezo (n = 16). All pts will undergo on-treatment (6-week) tumor biopsy. Treatment will be continued until disease progression and crossover is prohibited. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-1, biopsy-proven prostate adenocarcinoma, progressive metastatic disease per Prostate Cancer Working Group 3 (PCWG3), progression/intolerance to ≥ 1 novel antiandrogen in hormone-sensitive or CRPC setting, ineligible for docetaxel/cabazitaxel (progression within 12 months of taxane, pt refusal, investigator discretion), no uncontrolled comorbidity or history of pneumonitis/ILD. Arms A &amp; B will use two stage design for co-primary endpoints of progression-free survival at 6 months using PCWG3 (6m-PFS) and objective response rate (ORR). If ≥ 1/12 pts meet either co-primary endpoint, 2nd stage will open to enroll 15 more pts in that arm. Treatment will be deemed to have meaningful clinical activity (MCA) if ≥ 6/27 meet 6m-PFS or ≥ 5/27 have an ORR. This will provide 86% power for 6m-PFS (34% vs. 12%) and 85% power for ORR (30% vs. 10%) at a one-sided α = 0.08. For MCA in arm C, 16 patients treated with abema+atezo will provide 80-85% power for 6m-PFS (34% vs. 12%) at a one-sided α = 0.05 using a one-sample log-rank test. Primary safety endpoint is the incidence of dose-limiting toxicities in pts receiving abema+atezo. Key secondary endpoints are clinical benefit rate (ORR + stable disease), duration of response and overall survival in arms A and B, and safety events in all arms. Primary exploratory endpoint is comparison of tumoral FoxP3+/CD8+ ratio in pts treated with abema vs. abema + atezo. Additional exploratory endpoints will evaluate association between response and genomic alterations identified from tissue or circulating tumor-derived exosomes. Enrollment began in July 2021 and projected enrollment goal is 3 years (NCT04751929). Clinical trial information: NCT04751929.

A phase Ia/Ib study of talazoparib in combination with tazemetostat in metastatic castration-resistant prostate cancer (mCRPC).

TPS195 Background: Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in metastatic castration-resistant prostate cancer (mCRPC), and is linked to lineage plasticity and therapy resistance. In pre-clinical studies, EZH2 directly regulates DNA damage repair (DDR) gene expression, and pharmacologic inhibition of EZH2 sensitizes prostate cancer cells to genotoxic stress as induced by poly-ADP ribose polymerase (PARP) inhibition. The PARP inhibitor talazoparib and EZH2 inhibitor tazemetostat are currently under study in mCRPC, and we are conducting a phase 1 clinical trial of the combination. Methods: Phase 1a of the study will define the recommended phase 2 dose (RP2D) and phase 1b will better assess safety and preliminary clinical activity of the combination at the RP2D. Eligible patients must have progressive disease after at least one secondary hormonal therapy and taxane-based chemotherapy (or felt not to be more appropriate for taxane), have disease evaluable for response (PSA ≥ 2 ng/ml or measurable disease by RECIST 1.1) and have a metastatic lesion amenable to biopsy adequate for next generation sequencing. In phase 1a (n=9-18), the starting doses are talazoparib 0.75 mg daily and tazemetostat 600 mg BID, with dose escalation/de-escalation of both agents by up to 2 dose levels [DLs] based on a 3+3 design. The RP2D is the maximum tolerated dose (MTD) or DL +2 (talazoparib 1 mg daily + tazemetostat 800 mg BID) if the MTD is not reached. After 6 patients are treated at the RP2D, phase 1b will enroll an additional 20 patients to an expansion cohort. The primary endpoint of safety and tolerability is based on incidence of dose-limiting toxicities [DLTs] and incidence and grade of adverse events [AEs] by CTCAE version 5.0. For the secondary endpoint of overall response rate (ORR; defined as PSA reduction by ≥ 50% OR radiographic response by RECIST 1.1), with a sample size of 26 (6 patients from dose escalation and 20 from expansion), we deem talazoparib+tazemetostat effective if ORR is ≥ 5/26 (19%). The probability of concluding that the treatment strategy effective is 0.11 if its true response rate is 10% and at least 0.93 if the true response rate exceeds 30%. Mandatory pre-treatment and on-treatment (8-week) biopsies will undergo targeted genetic sequencing, transcriptomic profiling, ChIP (Chromatin ImmunoPrecipitation)-seq, and immunohistochemistry (IHC) for DDR and differentiation markers; blood specimens will undergo circulating cell-free DNA and circulating tumor cell profiling – these studies will nominate possible predictive biomarkers for therapeutic response and serve as pharmacodynamic markers of combined PARP and EZH2 inhibition. The goal of this study is to expand treatment options in mCRPC through a novel approach to exploit EZH2 as a therapeutic target through co-targeting the DDR response. Enrollment began in July 2021. Clinical trial information: NCT04846478.

FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (JCOG1804E)—Short-term results for cohorts C and D.

286 Background: The standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell carcinoma (ESCC) consists of CDDP + 5-FU (CF). Recently, neoadjuvant DTX plus CF (DCF) therapy has shown promising efficacy for locally advanced ESCC. In addition, immune checkpoint inhibitors (ICIs) have demonstrated a survival benefit in ESCC and potential as an NAC in several cancers, including lung, breast, skin, and bladder. We previously reported that neoadjuvant CF plus nivolumab (Nivo) therapy was tolerable and showed promising efficacy for ESCC; however, the efficacy of ICI with DCF as an NAC and the safety of subsequent surgery for ESCC patients remain unclear. Methods: FRONTiER is a multi-cohort phase I study designed to evaluate the safety and efficacy of ICI combined with NAC in ESCC. The eligibility criteria were histologically proven ESCC with cT1N1-3M0 or cT2-3N0-3M0 (8th-UICC TNM classification), patient age of 20-75 years, PS ≤1, and no prior cancer therapies. The primary endpoint was the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contained 5 experimental cohorts: cohort C received 3 courses of DTX (70 mg/m2), CDDP (70 mg/m2), and Nivo (360 mg/body) on day 1 and 5-FU (750 mg/m2) on days 1–5 every three weeks. Cohort D received one administration of Nivo (240 mg/body) 2 weeks before chemotherapy followed by the same regimen as cohort C. Results: Twelve patients were enrolled in cohort C (n = 6) and D (n = 6) (median age [range]: 60 [31-74] years, PS 0/1: 11/1, clinical stage I/II/III/IVA: 2/2/7/1). Only one patient in cohort D developed DLT (grade 3 dyspnea and rash); no other DLT were seen. Grade ≥3 adverse events were neutropenia (n = 1), leukopenia (n = 7), anorexia (n = 3), hyponatremia (n = 2), febrile neutropenia (n = 1), nausea (n = 1), and lymphopenia (n = 1) during NAC, and lung infection (n = 2), peritoneal infection (n = 1), anemia (n = 1), lymph leakage (n = 1), vagal reflex (n = 1), dyspnea (n = 1), rash (n = 1), septic shock (n = 1), pleural effusion (n = 1), and pneumatosis intestinalis (n = 1) during the postoperative period. No treatment-related deaths were observed. All patients received 3 courses of NAC, and 11 patients (91.7%) achieved an R0 resection without treatment interruption. One patient (16.7%) in cohort C and 3 patients (50.0%) in cohort D achieved pathological complete responses. Conclusions: Neoadjuvant DCF + Nivo with/without prior Nivo administration followed by surgery for locally advanced ESCC was well tolerated and showed an extremely promising efficacy. Clinical trial information: NCT03914443.

Impact of Body Composition on Prognosis and Dose-Limiting Toxicities on Metastatic Colorectal Cancer.

Sarcopenia is a progressive skeletal muscle disease, often present in oncological patients, that is associated with multiple adverse events such as worse prognosis, physical performance, and quality of life. Body composition evaluation by CT cross-section at the L3 vertebrae region appears to be a precise method to quantify skeletal muscle. The optimal cut-off for the definition of sarcopenia is not yet established, therefore the incidence of sarcopenia varies according to different studies. The main goal was to evaluate the presence of sarcopenia in patients with metastatic colorectal cancer (mCRC) and its impact on overall survival (OS) and dose-limiting toxicities (DLT). A retrospective cohort study of 178 patients with mCRC under first-line chemotherapy (ChT) in association with target therapy, in two hospital units, between January 2015 and December 2018. Skeletal mass area (SMA) was quantified with the NIH ImageJ software in CT cross-sectional images at the L3 vertebrae region. Statistical analysis was performed with IBM SPSS v25 software https://www.ibm.com/analytics/spss-statistics-software. The median age was 62 (SD ± 11) years old, 65% were men and 62.9% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. The cut-off value was established based on ROC analysis, with sarcopenia defined as SMI < 49.12 cm2/m2 for men and < 35.85 cm2/m2 for women. Despite the mean body mass index (BMI) of 25.71 (± 4.71) kg/m2, half of the patients presented sarcopenia. In a multivariate analysis using a Cox regression model, an association was observed between OS and higher ECOG PS (p = 0.014; HR 5.46, CI 95% [1.42–21.10]), neutrophil-to-lymphocyte ratio (NLR) >2.80 (p = 0.038; HR 2.20, CI 95% [1,05–4.62]), and sarcopenia (p = 0.01; HR 4.73, CI 95% [1.85–12.09]). Additionally, in a logistic regression model, age (p = 0.014; OR 1.09, IC 95% [1.02–1.16]) and sarcopenia (p= 0.030, OR 4.13, IC 95% [1.15-14.8]) were associated with higher incidence of DLT. The CT evaluation of the body composition at the L3 region allows for the quantification of sarcopenia, providing prognostic information and predictive value of DLT in patients with mCRC, although the establishment of optimal cut-off values are required for implementation in clinical practice. A multimodal strategy to delay muscle waste should be considered in these patients.

Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody–drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study

Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.

A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer

IntroductionPreclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC).MethodsIn this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150 mg oral daily [QD]), momelotinib was combined and dose escalated in a 3 + 3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK).ResultsEleven patients were enrolled across 3 dose levels of momelotinib (100 mg QD, 200 mg QD, and 100 mg twice daily [BID]). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1–2. The overall response rate was 54.5% (90% CI 27.1–80.0; all partial) and median progression-free survival was 9.2 months (90% CI 6.2–12.4). Momelotinib did not affect the PK of erlotinib.ConclusionsThe JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC.ClinicalTrials.gov identifierNCT02206763.