Dose-limiting Toxicity Rate Research Articles

First-In-Human Dose-Escalation Study of Fianlimab, an Anti-Lymphocyte Activation Gene-3 Antibody, with Cemiplimab in patients with advanced malignancies.

Preclinical data indicate that fianlimab (anti-lymphocyte activation gene-3) plus cemiplimab (anti-programmed cell death-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies. Adult patients received fianlimab 1-40 mg/kg ± cemiplimab 350 mg every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were rate of dose-limiting toxicities, adverse events (including immune-mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables. Seventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, 87% with fianlimab + cemiplimab, and 87% who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose-proportional, and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response; three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1600 mg Q3W (20 mg/kg in an 80 kg individual) is the selected dose for phase 2 and 3 studies. Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.

Abstract A004: A Phase 1B/2 trial of second line immunotherapy with pepinemab and avelumab for patients with metastatic pancreatic adenocarcinoma

Abstract Background: Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor prognosis despite maximal therapy and is recalcitrant to approved immunotherapies. In PDAC, Semaphorin 4D (SEMA4D) expression is prognostic in patients who have undergone surgical resection and correlates with tumor infiltration of activated CD8+ T-cells. Furthermore, preclinical studies suggest that monoclonal blockade of SEMA4D supports CD8+T cells tumoral infiltration and activation, sensitizing PDAC to immune checkpoint blockade (ICB). Thus, we hypothesized that a humanized anti-SEMA4D antibody (pepinemab) may improve disease control and responsiveness to ICB in patients with PDAC. Methods: We designed a phase Ib/II single-arm clinical trial to evaluate the safety, tolerability, and efficacy of pepinemab with anti-PD-L1 (avelumab) in patients with chemotherapy-refractory PDAC (NCT05102721). The study follows a dose de-escalation schema starting at a dose combination of 20mg/kg pepinemab and 800mg avelumab every two weeks. Patient accrual for phase 1b utilizes the Bayesian Optimal Interval design targeting a dose-limiting toxicity rate of 30% or less. After 16 subjects receive a given combination dose, a Simon’s two stage assessment of futility will be undertaken with expansion to phase 2 if 2 or more subjects demonstrate response. Treatment response is assessed via RECIST 1.1 criteria with surveillance CT prior to enrollment and after completion of two cycles (8 weeks). Baseline and on-treatment tumor biopsies (after completion of one cycle, 4 weeks) are performed to analyze changes in immune, stromal, and genomic profiles to elucidate mechanisms of treatment response and failure. Patient reported outcomes are incorporated (FACT-Hep and FAACT subdomains) to assess disease-specific symptoms. Results: A total of 14 patients have been enrolled to date. Three subjects withdrew from the study prior to completing the evaluable period (four weeks of treatment) and nine subjects terminated treatment due to disease progression. Two subjects continue to receive combination treatment pending evaluation of tumor response. Baseline and on-treatment biopsies have been obtained and stored for correlative analysis from 8 evaluable subjects. One treatment-related adverse event occurred though the patient was able to complete treatment without further events. No treatment-related toxicities have been encountered. Conclusions: Combining pepinemab with avelumab appears to be safe and tolerable to date. Nine of eleven patients demonstrated disease progression, though 1 of these 9 demonstrated mixed response with some lesions showing radiologic partial and even complete response. Overall treatment response, survival data, and correlative science forthcoming. Citation Format: Luis I Ruffolo, Matthew Byrne, Bailey Hilty, Brian A Belt, Yatee Dave, Paul Burchard, Terrence Fisher, Elizabeth E. Evans, Crystal Mallow, Megan Boise, Darren Carpizo, Jen Jen Yeh, David C Linehan, Daniel Mulkerin. A Phase 1B/2 trial of second line immunotherapy with pepinemab and avelumab for patients with metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A004.

Leveraging pharmacokinetic parameters as covariate in Bayesian logistic regression model to optimize dose selection in early phase oncology trial

ABSTRACT Dose selection and optimization in early phase of oncology drug development serves as the foundation for the success of late phases drug development. Bivariate Bayesian logistic regression model (BLRM) is a widely utilized model-based algorithm that has been shown to improve the accuracy for identifying recommended phase 2 dose (RP2D) based on dose-limiting-toxicity (DLT) over traditional method such as 3 + 3. However, it remains a challenge to optimize dose selection that strikes a proper balance between safety and efficacy in escalation and expansion phase of phase I trials. In this paper, we first use a phase I clinical trial to demonstrate how the variability of drug exposure related to pharmacokinetic (PK) parameters among trial participants may add to the difficulties of identifying optimal dose. We use simulation to show that concurrently or retrospectively fitting BLRM model for dose/toxicity data from escalation phase with dose-independent PK parameters as covariate lead to improved accuracy of identifying dose level at which DLT rate is within a prespecified toxicity interval. Furthermore, we proposed both model- and rule-based methods to modify dose at patient level in expansion cohorts based on their PK/exposure parameters. Simulation studies show this approach leads to higher likelihood for a dose level with a manageable toxicity and desirable efficacy margin to be advanced to late phase pipeline after being screened at expansion phase of phase I trial.

First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors

Rationale of the trialAlthough the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid...

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

An open-label, multicenter, phase Ib/II study of the ATR inhibitor SC0245 in combination with irinotecan in patients with relapsed and refractory extensive stage small cell lung cancer (ES-SCLC).

8102 Background: Ataxia telangiectasia and Rad3 related (ATR) is activated in response to replication stress induced by topoisomerase 1 inhibitors (TOP1i) and other DNA damaging agents. SC0245 is a novel potent ATR inhibitor, showing synergistic inhibitory effects when combined with TOP1i in DMS-114 and H446 small cell lung cancer. This is the first report on an ongoing phase Ib/II study of SC0245 in combination with irinotecan (IRI) in patients (pts) with ES-SCLC (ClinicalTrials.gov: NCT05731518). Methods: Multiple escalating doses of SC0245 are being administered orally with a fixed dose of IRI. Pts are being enrolled into five escalating dose cohorts (80 mg once daily (QD), 120 mg QD, 80 mg twice daily (BID), 120 mg BID, 160 mg BID) using a BOIN design. SC0245 is administered daily for 3 days weekly x 3 (e.g, Days 1-3, 8-10 and 15-17) with IRI 80 mg/m2 on Days 1, 8 and 15. Cycles are repeated every 4 weeks. The primary endpoint is the rate of dose-limiting toxicity (DLT). Tumor assessments are being performed every 8 weeks using RECIST v1.1. Dose expansion in ES-SCLC patients will follow after definition of the recommended phase 2 dose (RP2D). Results: As of the data cut-off-date (December 21, 2023), 15 pts (median age, 65; male, 73.3%) with previously treated solid tumors have been enrolled, with 3, 4, 3 and 5 pts in 80mg QD, 120mg QD, 80mg BID and 120 mg BID dose cohorts, respectively. 12 of 15 pts were DLT evaluable, and one DLT event (Grade 3 febrile neutropenia) occurred in the 80 mg QD dose cohort. Cytopenia, diarrhea, and liver function test elevations, were the main adverse events (AEs) experienced in 73.3%, 46.7% and 40% pts, respectively. Most AEs were grade 1 or 2 in severity and manageable. The only ≥ Grade 3 TRAEs experienced by more than 2 subjects has been leukopenia (3/15, 20.0%). No drug-related deaths occurred. Among the 9 pts who were evaluable for tumor response, one confirmed partial response (PR) was reported in a pt with ES-SCLC (progressed on prior 1st line of etoposide + carboplatin + serplulimab treatment) treated in the 120mg QD dose cohort, and the response sustained for 32+ weeks; five pts (5/9, 55.6%) had stable disease (SD) as their best response. PK characteristics indicated that SC0245 was rapidly absorbed (median Tmax, 1.0 to 2.0 h), and drug exposure was proportional to dose for the QD and BID regimens. No drug-drug interactions (DDI) between SC0245 and either IRI or its active metabolite SN38 were observed. Conclusions: SC0245 exhibited favorable safety and PK characteristics when administered in combination with IRI at doses ranging from 80mg QD to 120mg BID and the regimen has demonstrated preliminary antitumor activity in ES-SCLC, supporting further evaluation of the regimen in ES-SCLC and other relevant malignancies. Clinical trial information: NCT05731518 .

Xevinapant with radiation and concurrent carboplatin and paclitaxel in patients ineligible for cisplatin with locoregionally advanced squamous cell carcinoma of the head and neck (EXtRaCT study).

TPS6126 Background: Locoregionally advanced (LA) head and neck cancer (HNC) patients undergoing chemoradiotherapy (CRT) who are ineligible for cisplatin have comparatively poor outcomes, with only ~40% alive at 5 years. There is an urgent unmet need to improve survival in these vulnerable patients with no standard therapeutic approach. Xevinapant, an oral inhibitor of XIAP and cIAP1/2, sensitizes cancer cells to apoptosis. Randomized phase II results in patients eligible for cisplatin combining xevinapant with CRT showed improved locoregional control, manageable toxicity, and promising survival outcomes. (Sun et al. Lancet Oncol. 2020) The current trial aims to extend these benefits to patients ineligible for cisplatin using xevinapant with carboplatin-paclitaxel-based CRT, hypothesizing safety and tolerability in this high-risk group. Methods: This phase I dose escalation/expansion study investigates xevinapant combined with carboplatin and paclitaxel to treat LA HNC in patients ineligible for cisplatin. Key eligibility includes previously untreated LA HNC and specific cisplatin ineligibility criteria, including >=70yo with moderate to severe comorbidity or vulnerability (Geriatric-8 score ≤ 14 and/or CARG score ≥ 30%) or <70yo with severe comorbidity and/or vulnerability, or >=18yo with an absolute contraindication to cisplatin. The treatment regimen comprises escalating doses of oral xevinapant (50-200 mg daily) on days 1-14 of a 21-day cycle for 3 cycles concurrent with CRT and 3 cycles adjuvant, weekly carboplatin AUC 1.5 IV, and paclitaxel 30 mg/m2 IV for 7 doses, and radiotherapy to 70 Gy in standard 2Gy fractions over 7 weeks with primary endpoint of tolerability and recommended phase 2 dose. A Bayesian-modified toxicity probability interval design will identify the maximum tolerated dose (MTD), targeting a 25% dose-limiting toxicity rate, with a sample size of 24 patients in dose-finding. 18 additional patients will be enrolled in the dose-expansion cohort at the MTD, totaling 42 patients. Secondary objectives include safety, response, progression-free, overall survival, and locoregional and distant control. Exploratory aims: in-clinic geriatric evaluations (Katz ADL, Lawton iADL, MMSE), QoL surveys, symptom tracking via smartphone, and wearable-derived steps and sarcopenia assessment. Recruitment began 02/2024. Clinical trial information: NCT06110195 .

Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.

3091 Background: RYZ101 (225Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improved therapeutic index. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Herein, we report updated results from the phase Ib portion of the trial. Methods: The phase Ib portion of the trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level –1 90 kBq/kg; Level –2 60 kBq/kg. DLT was assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions/safety data were overseen by a Data Review Committee. Tumor response was assessed locally by RECIST v1.1. Results: 17 patients have received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 30 June 2023, the most frequent TEAEs were nausea (58.8%) and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (none were treatment related); grade ≥3 AEs occurred in 9 patients (5 were treatment related). No AEs led to treatment discontinuation. 4 patients had TEAEs leading to dose modification, dose hold, and/or delays. The confirmed objective response rate was 29.4% (n=5; all partial responses); 1 patient had an unconfirmed partial response. 8 patients (47.1%) had stable disease and 3 patients (17.6%) had progressive disease. Updated safety and efficacy data, including duration of response and progression-free survival, will be presented. Conclusions: RYZ101 was well tolerated and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy. Longer-term safety and efficacy data will be presented. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 .

Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in patients with HER2 low/ultra-low/null metastatic breast cancer.

TPS1120 Background: In the DAISY study (NCT04132960), meaningful clinical response was observed with Trastuzumab deruxtecan (T-DXd) in HER2 IHC 0 MBC. Valemetostat is an oral, selective dual inhibitor of enhancer of zeste homolog 1 and 2 (EZH1/2) methyltransferases that specifically methylate histone H3 lysine 27. EZH2-mediated PP2A inactivation confers resistance to HER2-targeted therapy. Additionally, valemetostat upregulates Schlafen11 (SLFN11), a putative DNA/RNA helicase, that regulates the sensitivity to DNA damaging agents such as topoisomerase I inhibitors. Based on these preclinical studies, this study examines the safety and anti-tumor activity of valemetostat in combination with T-DXd in subjects with HER2 low/ultra-low/null MBC. Methods: This is a single-arm, phase-1b study to evaluate the safety and clinical activity of T-DXd in combination with valemetostat in patients with HER2 low/ultra-low/null MBC (NCT05633979). The dosing for T-DXd is 5.4 mg/kg Q3W administered intravenously as indicated for current clinical use by FDA approval. Valemetostat will be evaluated at three dose levels (100 mg, 150 mg, and 200 mg orally), with a starting dose (level 1) at 100 mg QD. The dose-limiting toxicity (DLT) evaluation period will be the first 2 treatment cycles (42 days). Major eligibility criteria: Pathologically confirmed HER2 low/ultra-low/null breast cancer; ECOG performance status ≤1; Measurable disease; Received at least one line of chemo in the metastatic setting; Progressed and would no longer benefit from endocrine therapy; Normal organ and marrow function. Exclusion criteria: symptomatic brain metastases, interstitial lung disease, cord compression, prior treatment with any anti-HER2 therapy. Objectives: To evaluate the safety and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE); To evaluate the objective response rate (ORR); To determine the duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS); To evaluate the pharmacokinetics and pharmacodynamic markers. Statistical methods: Approximately 12 evaluable patients will be enrolled for the dose-escalation portion based on the Bayesian optimal interval design with a target DLT rate of 25%. Patients will be enrolled in cohorts of 3. The expansion will be performed at the RDE using the 2-stage Bayesian optimal dose-expansion design. In the first stage, 13 evaluable patients will be enrolled. If <5 patients respond in the first stage, the study will be stopped for futility. If ≥5 responses are observed, 13 additional evaluable patients will be enrolled. If 11 or more responses are observed among 26 patients, the treatment will be regarded as promising. This two-stage design yields 78% power under the alternative hypothesis of ORR = 50% (null ORR = 30%) while controlling the one-sided type I error at 10%. Clinical trial information: NCT05633979 .

Abstract PO4-19-11: A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer

Abstract Background The androgen receptor (AR) is expressed in approximately 30% of breast cancers. Phase I and II trials of bicalutamide in HR-negative and enzalutamide in both triple negative breast cancer (TNBC) and hormone receptor (HR) positive populations have shown safety and favorable clinical benefit rates (CBR). Additionally, cell cycle (CC) inhibitors, such as abemaciclib, have demonstrated improved progression free survival (PFS) for patients with HR-positive metastatic breast cancer (MBC) in combination with ET in the first line and subsequent lines of therapy. A preclinical study showed that anti-androgen therapies enhanced CKD4/6 induced cytostatic effect in AR-positive TNBC cell lines. We performed a retrospective, institutional study evaluating metastatic HR+ tumor samples with immunohistochemistry (IHC) from patients treated with CDK4/6 inhibitor, palbociclib. We found a statistically significant increase in event free survival (EFS) for those that had any expression of AR (>0%, median EFS 19 months vs 5 months, HR 0.26, p=0.01). Additionally, AR expression was associated with intact phosphorylated retinoblastoma (Rb) expression (100%, P=0.02), which may represent a mechanism by which CC inhibition is effective in AR+ MBC. Trial Design NCT 05095207 is an ongoing, Phase Ib/II, open label, multi-center study. The primary objective for the phase I portion is to determine the recommended phase II dose (RP2D) of abemaciclib in combination with bicalutamide. The primary objective for the phase II portion is to determine the disease control rate (DCR) at 6-month treatment with abemaciclib and bicalutamide. Patients with HER2-negative MBC who are AR+ (IHC >1%) are eligible. HR-positive participants must have had one prior line of ET in the metastatic setting and no more than 2 prior lines of cytotoxic chemotherapy. HR-negative participants may have had up to 4 prior lines of cytotoxic chemotherapy. In the Phase I portion, up to 12 patients are given abemaciclib 100 mg oral, twice daily on days 1 to 28 and bicalutamide 150 mg oral, daily on days 1 to 28. If there is no toxicity after cycle 1 for the first 3 patients, the dose of abemaciclib will increase to 150 mg twice daily. However, if there is a dose limiting toxicity (DLT) within the first cycle (28 days) of therapy, the dose will decrease to 50 mg twice daily. In the Phase II portion, 51 patients will receive abemaciclib at the RP2D twice daily in addition to bicalutamide 150 mg daily on days 1 to 28. The estimated study duration is 36 months. The drugs will be administered until disease progression or unacceptable toxicity. The primary end points include the DLT and the RP2D for abemaciclib administered with bicalutamide and the DCR at 6 months. The secondary end points include the frequency of adverse effects, the DCR stratified by HR status, and PFS. Exploratory endpoints are to determine whether Ki67, cyclin D1, p16, and phosphorylated Rb expression at baseline are predictors of response to abemaciclib and to determine potential mechanisms for resistance to treatment. For Phase Ib, we will utilize the Bayesian optimal interval (BOIN) design, the RP2D will be selected as the dose closest to the target toxicity rate of 0.3. The observed DLT rate at the current dose is ≤ 0.236, the next cohort will be treated at the next higher dose level, if it is ≥ 0.359 the next cohort will be treated with the next lower dose level. For Phase II, we will assess the DCR using a Simon 2 stage optimal design. If among the 46 evaluable patients, 12 or fewer achieve disease control, the treatment will be rejected, however if 13 or more have disease control, the treatment will be considered worthy for further study. We define inactivity as DCR of 0.20 and activity as DCR of 0.35. To date, the study has recruited 21 participants, the goal accrual is 60 patients. Citation Format: Nicole Casasanta, Chrystal Landry, Theresa Shao, Paula Klein, Julie Fasano, Aarti Bhardwaj, Natalie Berger, Erin Moshier, Gargi Atul Joshi, Rita Vaccaro, Joseph Sparano, Amy Tiersten. A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-11.

Abstract PO3-19-10: Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in subjects with HER2 low/ultra-low/null metastatic breast cancer

Abstract Background Low HER2-expressing breast cancers have traditionally been classified as HER2-negative and treated as TNBC or hormone receptor (HR)-positive. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, composed of an anti-HER2 antibody conjugated to topoisomerase I payload, is approved for clinical use in HER2-low (IHC 1+ or IHC 2+/ISH negative) metastatic breast cancer (MBC). In the DAISY study (NCT04132960), meaningful clinical response was observed with T-DXd in HER2 IHC 0 MBC. Valemetostat is an oral, selective dual inhibitor of enhancer of zeste homolog 1 and 2 (EZH1/2, methyltransferases that specifically methylate histone H3 lysine 27. It is currently approved for patients with relapsed or refractory adult T-cell leukemia/lymphoma in Japan. EZH2-mediated PP2A inactivation has been shown to confer resistance to HER2-targeted therapy. Additionally, valemetostat has been shown to upregulate Schlafen11 (SLFN11), a putative DNA/RNA helicase, that regulates the sensitivity to DNA damaging agents such as topoisomerase I inhibitors. Consequently, this study examines the safety and anti-tumor activity of valemetostat in combination with T-DXd in subjects with HER2 low/ultra-low/null MBC. Trial Design This is a single-arm, phase-1b study to evaluate the safety and clinical activity of T-DXd in combination with valemetostat in patients with HER2 low/ultra-low/null MBC. The dosing for T-DXd is 5.4 mg/kg Q3W administered intravenously as indicated for current clinical use. Valemetostat will be evaluated at three dose levels (100 mg, 150 mg, and 200 mg orally), with starting dose (level 1) at 100 mg QD. The dose-limiting toxicity (DLT) evaluation period will be the first 2 treatment cycles (42 days). Eligibility criteria Specific aims Statistical methods Approximately 12 evaluable patients will be enrolled for the dose-escalation portion based on the Bayesian optimal interval design with a target DLT rate of 25%. Patients enrolled in cohorts of 3. The expansion will be performed at the RDE using the 2-stage Bayesian optimal dose-expansion design. In the first stage, 13 evaluable patients (including those treated at the RDE in the dose-escalation part) will be enrolled. If < 5 patients respond in the first stage, the study will be stopped for futility. If ≥ 5 responses are observed, 13 additional evaluable patients will be enrolled. If 11 or more responses are observed among the total of 26 patients the treatment will be regarded as promising. This two-stage design yields 78% power under the alternative hypothesis of ORR=50% (null ORR = 30%) while controlling the one-sided type I error at 10%. Contact information for people with a specific interest in the trial sdamodaran@mdanderson.org (NCT05633979) Citation Format: Senthil Damodaran, Toshiaki Iwase, Angela Marx, Jie Willey, Funda Meric-Bernstam, Debu Tripathy, Carlos Barcenas, Jangsoon lee, Naoto Ueno. Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in subjects with HER2 low/ultra-low/null metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-10.

Abstract PS17-06: A phase I trial of the PI3K inhibitor (PI3Ki) copanlisib and fulvestrant in combination with continuous or intermittent abemaciclib in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer

Abstract Background: Activation of the phosphoinositide 3-kinase (PI3K) pathway is a prominent resistance mechanism to endocrine therapy and CDK4/6 inhibition (CDK4/6i) in ER+, HER2- breast cancer. There is reciprocal crosstalk between PI3K and cell cycle regulatory pathways. Triplet therapy that targets ER, CDK4/6, and PI3K prevents or delays disease progression in preclinical models of ER+, HER2- breast cancer. However, the toxicities of triplet therapy hinder its clinical development. Copanlisib (COP) is an intravenous (IV) PI3Ki with potent activity against α and δ isoforms. Intermittent high-dose PI3Ki is expected to be less toxic and more effective than continuous daily dosing. We set out to determine the recommended phase 2 dose (RP2D) for the COP/Fulvestrant (FUL)/Abemaciclib (ABE) combination. Methods: Eligible patients (pts) included men or women with ER+, HER2- metastatic breast cancer (MBC), with no more than 1 prior chemotherapy in the metastatic setting, and no limits on prior endocrine or targeted therapy. Prior FUL, CDK4/6i and PI3K/mTORi were allowed. Pts with HbA1c >8.5% were excluded. Pts received FUL 500 mg IM standard dosing and COP/ABE at assigned doses. Premenopausal women also received a GnRH agonist. Dose-limiting toxicity (DLT) was assessed during the first 28-day cycle. Adverse events (AEs) were graded according to NCI-CTCAE v5.0. Dose escalation/de-escalation was based on continual reassessment (CRM) and the RP2D was defined as the dose with the highest probability of the DLT rate within the acceptable 25~35%. Results: Between June 2020 and June 2023, 24 pts with ER+, HER2- MBC were enrolled. Table 1 shows the dose levels (DLs) and DLTs. The first 10 pts were enrolled to Part A on two consecutive DLs of COP (DL1: 45 mg IV D1 and D15, n=7; DL2: 45 mg IV D1, D8, and D15, n=3), with ABE fixed at 100 mg PO BID continuously. DL2a exceeded the maximum tolerated dose (MTD). DL1a was tolerable based on Cycle 1 AEs. However, during subsequent cycles, only 1 of the 7 pts in DL1a maintained the intended dose of ABE due to neutropenia, others reduced ABE to 50mg bid (n=5) or discontinued (n=1). This triggered a protocol amendment, adding Part B with ABE administered 5 days on and 2 days off (5-on/2-off) intermittent schedule. 14 pts were enrolled to Part B in 2 consecutive DLs of COP (DL1b: n=7; DL2b: n=7), the same as in Part A. ABE was fixed at 100 mg PO Bid 5-on/2-off. DL2b exceeded the MTD. DL1b was tolerable based on Cycle 1 AEs. In addition, in subsequent cycles, only 1 of 7 pts on DL1b required dose reduction of ABE to 50mg bid. RP2D is therefore defined as DL1b. Grade (G) 4 AEs were rare. The most common all cycle G3 AEs included transient hypertension (45%), rash (30%), anemia (25%), neutropenia (25%), and AST elevation (20%). As of 6/14/2023, 22 pts, with a median of 1 prior metastatic regimen (range 0-5), prior CDK4/6i in 18 (82%), liver mets in 8 (36%), and PIK3CA mutation in 8 (50%) of 16 pts with known mutation status, were evaluable for response. There were 5 partial responses and 3 stable diseases lasting for ≥24 weeks. Clinical benefit rate was 36.4% (8/22, 95%CI: 17.19% ~ 59.34%). Responses were observed in pts regardless of prior CDK4/6i, FUL, or PIK3CA mutation. Conclusion: COP/FUL/intermittent ABE can be safely administered with fair overall tolerability. Preliminary anti-tumor activity was observed, which will be further examined in the randomized phase II trial (NCT 03939897). Table 1 Dose-limiting Toxicities by Dose Level Citation Format: Cynthia Ma, Jingqin Luo, Jessica Moss, Maryann Kwa, Ritesh Parajuli, Katia Khoury, Emily Douglas, Ashley Frith, Caron Rigden, Foluso Ademuyiwa, Shana Thomas, Brittney Haas, Gerburg Wulf, Claire Dees, Rabih Said. A phase I trial of the PI3K inhibitor (PI3Ki) copanlisib and fulvestrant in combination with continuous or intermittent abemaciclib in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-06.

Abstract PO3-20-04: A first-in-human study of the highly selective PI3Kα inhibitor RLY-5836 in patients with advanced breast cancer and other solid tumors

Abstract Background: Oncogenic activation of PI3Kα is a common driver event in solid tumors. Although PI3Kα is a validated therapeutic target, there is no approved highly selective inhibitor that targets mutant PI3Kα. Alpelisib, a non-selective orthosteric PI3Kα inhibitor, is approved in combination with fulvestrant for patients with PIK3CA-mutant, ER+, HER2– advanced breast cancer. Inhibition of wild-type PI3Kα causes hyperglycemia, limiting the tolerability, dosing, and efficacy of alpelisib. RLY-5836 is the second allosteric, selective pan-mutant PI3Kα inhibitor under clinical investigation. It is molecularly distinct with differentiated pharmaceutical properties compared to RLY-2608. This first-in-human study aims to further explore the tolerability and efficacy of highly selective PIK3CA-mutant inhibition as monotherapy and in combination treatment. Methods: This multicenter, open-label study is designed to evaluate the safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics (PK) and preliminary anti-tumor efficacy of RLY-5836 as a single agent and in various combinations. A Bayesian Optimal Interval design is used for dose escalation, followed by a dose expansion part. As monotherapy, RLY-5836 will be investigated in pts with advanced solid tumors harboring a PIK3CA mutation (Arm 1) per local assessment (blood and/or tumor). In pts with PIK3CA-mutant, HR+, HER2– advanced or metastatic breast cancer, RLY-5836 combination arms will include anti-estrogen therapy with or without CDK4/6 inhibition: fulvestrant (Arm 2), and fulvestrant + CDK4/6 inhibitor(s) (Arms 3–5). RLY-5836 is administered orally, continuously in 28-day cycles until disease progression or study discontinuation. Enrollment criteria include age ≥18 years, ECOG PS 0–1, and measurable disease (Arm 1) or evaluable disease (Arms 2–5) per RECIST version 1.1. Participants in the combination arms are required to have received prior treatment with ≥1 CDK4/6 inhibitor and ≥1 anti-estrogen therapy. Prior treatment with a PI3Kα inhibitor is an exclusion criterion for the dose expansion parts of all arms. Planned overall sample size is ~220 pts (~145 pts for the dose escalation, and ~15 pts in each dose expansion arm). Primary endpoints are the MTD, RP2D and overall safety profile of RLY-5836, either as a single agent or in combination. The MTD will be determined as the dose with a dose-limiting toxicity rate closest to the target toxicity rate (30%) in Cycle 1. Secondary endpoints include PK and efficacy parameters. Statistical analyses will be descriptive. This study (NCT05759949) is enrolling in the United States. For further information, please contact clinicaltrials@relaytx.com. Funding source: This study is funded by Relay Therapeutics, Cambridge, MA, United States. Citation Format: Andreas Varkaris, Steven Isakoff, Cesar A. Perez, Bert O'Neil, Erika Hamilton, Erin Conlin, Gege Tan, Xiaoyan Li, Alison Timm, Ramin Samadani, Erika Puente-Poushnejad, Eunice Kwak, Brenton G. Mar, Alison M. Schram. A first-in-human study of the highly selective PI3Kα inhibitor RLY-5836 in patients with advanced breast cancer and other solid tumors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-04.

The 3 + 3 design in dose-finding studies with small sample sizes: Pitfalls and possible remedies.

In the last few years, numerous novel designs have been proposed to improve the efficiency and accuracy of phase I trials to identify the maximum-tolerated dose (MTD) or the optimal biological dose (OBD) for noncytotoxic agents. However, the conventional 3+3 approach, known for its and poor performance, continues to be an attractive choice for many trials despite these alternative suggestions. The article seeks to underscore the importance of moving beyond the 3+3 design by highlighting a different key element in trial design: the estimation of sample size and its crucial role in predicting toxicity and determining the MTD. We use simulation studies to compare the performance of the most used phase I approaches: 3+3, Continual Reassessment Method (CRM), Keyboard and Bayesian Optimal Interval (BOIN) designs regarding three key operating characteristics: the percentage of correct selection of the true MTD, the average number of patients allocated per dose level, and the average total sample size. The simulation results consistently show that the 3+3 algorithm underperforms in comparison to model-based and model-assisted designs across all scenarios and metrics. The 3+3 method yields significantly lower (up to three times) probabilities in identifying the correct MTD, often selecting doses one or even two levels below the actual MTD. The 3+3 design allocates significantly fewer patients at the true MTD, assigns higher numbers to lower dose levels, and rarely explores doses above the target dose-limiting toxicity (DLT) rate. The overall performance of the 3+3 method is suboptimal, with a high level of unexplained uncertainty and significant implications for accurately determining the MTD. While the primary focus of the article is to demonstrate the limitations of the 3+3 algorithm, the question remains about the preferred alternative approach. The intention is not to definitively recommend one model-based or model-assisted method over others, as their performance can vary based on parameters and model specifications. However, the presented results indicate that the CRM, Keyboard, and BOIN designs consistently outperform the 3+3 and offer improved efficiency and precision in determining the MTD, which is crucial in early-phase clinical trials.

Abstract CT037: A phase I investigator-initiated trial of evorpacept (ALX148), lenalidomide and rituximab for patients with relapsed or refractory B-cell non-Hodgkin lymphoma

Abstract Introduction. We have recently demonstrated that pro-tumoral SIRPα+ macrophages may mediate resistance to lenalidomide and rituximab (R2) in patients (pts) with relapsed or refractory (RR) B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel high-affinity CD47 blocker that abrogates the ‘do-not-eat-me signal’ provided to SIRPα+ macrophages. In a phase I trial including 33 pts with RR B-NHL it was well tolerated in combination with rituximab. We hypothesized that evorpacept and R2 will be synergistic, and the combination will be safe and effective for the treatment of pts with RR B-NHL. Methods. This single arm phase I study (NCT05025800) was conducted between 11/2021 and 9/2023 (data cut-off 12/2023). Adult pts with RR B-NHL who had received at least 2 prior lines of systemic therapy (1 in case of indolent B-NHL [iNHL]) were included. Evorpacept was administered intravenously (IV), in a 28-day cycle, for 12 cycles, at two dose levels (DL): 30 mg/Kg on day (D) 1 and D15 (DL1), or 60 mg/Kg on day 1 (DL2); rituximab IV was given weekly during cycle 1, and on D1 during cycles 2-6; lenalidomide was given orally on D1-21 during cycles 1-6. Dose limiting toxicity (DLT) was evaluated according to CTCAE v5 during cycle 1 and a Bayesian Optimal Interval design was used, with a target DLT rate of 0.3. Response was assessed according to Lugano 2014 criteria. Results. Twenty pts were included in the study. Median age was 61 (27-85), 10 (50%) were male, and 7 (35%) were non-white; 15 (75%) had follicular lymphoma, 3 (15%) marginal zone lymphoma, 1 (5%) mantle cell lymphoma, and 1 (5%) Richter Syndrome; 20 (100%) had previously received an anti-CD20 monoclonal antibody, 13 (72%) chemoimmunotherapy, and 15/18 (83%) iNHL pts had intermediate-high FLIPI. Three pts were treated at DL1, 17 at DL2, and no DLT was observed. The most common grade 3-4 adverse events included: neutropenia (55%), infections (30%), ALT increase (15%), AST increase (10%), skin rash (10%), and anemia (10%). Eight (40%) pts experienced a cycle delay, mainly due to grade (G) 1 AST/ALT elevation; 6 (30%) required a dose reduction for lenalidomide, none for evorpacept; 1 pt discontinued treatment after 1 cycle due to G3 lenalidomide-associated myocarditis. Sixteen (80%) pts achieved CR and best overall response rate was 90%. After a median follow-up of 16 months (95% CI, 12-20 months), 1-year PFS rate was 70% and 1-year OS rate was 90%. Conclusions. The combination of evorpacept and R2 is well tolerated in pts with RR B-NHL, with similar toxicity and promising anti-tumoral activity as compared to historical CR rates with R2 alone (34%). Bulk RNA sequencing and multiplex immunofluorescence are being performed on tissue biopsies collected before and during treatment, to characterize its effects on the tumor immune microenvironment. A phase 2 study investigating its efficacy in pts with previously untreated iNHL is now enrolling. Citation Format: Paolo Strati, Lei Feng, Dai Chihara, Jason Westin, Sairah Ahmed, Luis Fayad, Jared Henderson, Jeffrey Davidson, Elizabeth McChesney, Loretta Nastoupil, Sattva Neelapu, Christopher Flowers. A phase I investigator-initiated trial of evorpacept (ALX148), lenalidomide and rituximab for patients with relapsed or refractory B-cell non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT037.

Hydroxyurea dose optimisation for children with sickle cell anaemia in sub-Saharan Africa (REACH): extended follow-up of a multicentre, open-label, phase 1/2 trial

Realizing Effectiveness Across Continents with Hydroxyurea (REACH) is an open-label non-randomised trial of hydroxyurea (hydroxycarbamide) in children with sickle cell anaemia in sub-Saharan Africa. The short-term results of REACH on safety, feasibility, and effectiveness of hydroxyurea were published previously. In this paper we report results from extended hydroxyurea treatment in the REACH cohort up to 8 years. In this open-label, non-randomised, phase 1/2 trial, participants were recruited from four clinical sites in Kilifi, Kenya; Mbale, Uganda; Luanda, Angola; and Kinshasa, Democratic Republic of Congo. Eligible children were 1-10 years old with documented haemoglobin SS or haemoglobin Sβ zero thalassaemia, weighing at least 10 kg. Participants received fixed-dose hydroxyurea of 17.5 (±2.5) mg/kg per day for 6 months (fixed-dose phase), followed by 6 months of dose escalation (2·5-5·0 mg/kg increments every 8 weeks) as tolerated, up to 20-35 mg/kg per day (maximum tolerated dose; MTD), defined as mild myelosuppression. After the MTD was reached, hydroxyurea dosing was optimised for each participant on the basis of changes in bodyweight and laboratory values over time (MTD with optimisation phase). After completion of the first 12 months, children with an acceptable toxicity profile and favourable responses were given the opportunity to continue hydroxyurea until the age of 18 years. The safety and feasibility results after 3 years has been reported previously. Here, haematological responses, clinical events, and toxicity rates were compared across the dosing phases (fixed-dose hydroxyurea vs MTD with optimisation phase) as protocol-specified outcomes. REACH is registered on ClinicalTrials.gov (NCT01966731) and is ongoing. We enrolled 635 children between July 4, 2014, and Nov 11, 2016. 606 children were given hydroxyurea and 522 (86%; 266 [51%] boys and 256 [49%] girls) received treatment for a median of 93 months (IQR 84-97) with 4340 patient-years of treatment. The current (Oct 5, 2023) mean dose is 28·2 (SD 5·2) mg/kg per day with an increased mean haemoglobin concentration (7·3 [SD 1·1] g/dL at baseline to 8·5 [1·5] g/dL) and mean fetal haemoglobin level (10·9% [SD 6·8] to 23·3% [9·5]) and decreased absolute neutrophil count (6·8 [3·0] × 109 cells per L to 3·6 [2·2] × 109 cells per L). Incidence rate ratios (IRR) comparing MTD with fixed-dose hydroxyurea indicate decreased vaso-occlusive episodes (0·60; 95% CI 0·52-0·70; p<0·0001), acute chest syndrome events (0·21; 0·13-0·33; p<0·0001), recurrent stroke events (0·27; 0·07-1·06; p=0·061), malaria infections (0·58; 0·46-0·72; p<0·0001), non-malarial infections (0·52; 0·46-0·58; p<0·0001), serious adverse events (0·42; 0·27-0·67; p<0·0001), and death (0·70; 0·25-1·97; p=0·50). Dose-limiting toxicity rates were similar between the fixed-dose (24·1 per 100 patient-years) and MTD phases (23·2 per 100 patient-years; 0·97; 0·70-1·35; p=0·86). Grade 3 and 4 adverse events were infrequent (18·5 per 100 patient-years) and included malaria infection, non-malarial infections, vaso-occlusive pain, and acute chest syndrome. Serious adverse events were uncommon (3·6 per 100 patient-years) and included malaria infections, parvovirus-associated anaemia, sepsis, and stroke, with no treatment-related deaths. Hydroxyurea dose escalation to MTD with dose optimisation significantly improved clinical responses and treatment outcomes, without increasing toxicities in children with sickle cell anaemia in sub-Saharan Africa. US National Heart, Lung, and Blood Institute and Cincinnati Children's Research Foundation.

A phase 1 trial of the MEK inhibitor selumetinib in combination with pembrolizumab for advanced or metastatic solid tumors

SummaryMEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (anti‒PD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1‒14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov, NCT03833427.

A phase 1b/2 trial of pepinemab and avelumab as second line therapy for patients with metastatic pancreatic adenocarcinoma.

TPS712 Background: Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor prognosis despite maximal therapy and is unresponsive to immune checkpoint blockade (ICB). This failure of response is hypothesized to be driven in part by the characteristic immunosuppressive tumor microenvironment. In PDAC, Semaphorin 4D (SEMA4D) expression is prognostic in patients who have undergone surgical resection and correlates with tumor infiltration of activated CD8+ T-cells. Additionally, preclinical models suggest that antibody-mediated SEMA4D blockade promotes tumoral infiltration and activation of CD8+ T-cells and sensitizes PDAC to ICB, with improved overall survival with standard of care chemotherapy and ICB in combination with pepinemab (humanized anti-SEMA4D). Thus, we hypothesized that pepinemab may improve clinical outcomes in PDAC by sensitizing tumors to ICB. Methods: We designed a phase Ib/II single-arm clinical trial to evaluate the safety, tolerability, and efficacy of humanized anti-SEMA4D (pepinemab) with anti-PD-L1 (avelumab) in patients with chemotherapy-refractory PDAC. Patients must have failed first-line 5-fluorouracil or gemcitabine-based combination chemotherapy. The study follows a dose de-escalation schema starting at a dose combination of 20mg/kg pepinemab and 800mg avelumab every two weeks. Patient accrual for phase 1b utilizes the Bayesian Optimal Interval Design (BOIN) targeting a dose-limiting toxicity rate of 30% or less. After 16 subjects receive a given combination dose, a Simon’s two stage assessment of futility will be undertaken with expansion to phase 2 if 2 or more subjects demonstrate response. The trial is designed to evaluate a total cohort of 40 subjects and powered to detect a response rate of 23% or greater, with alpha set at 0.1% and 80% power. Treatment response is assessed via RECIST 1.1 criteria with surveillance CT prior to enrollment and after completion of two cycles (8 weeks). Baseline and on-treatment tumor biopsies (after completion of one cycle, 4 weeks) are performed to analyze changes in immune, stromal, and genomic profiles to elucidate mechanisms of treatment response and failure. Patient reported outcomes are incorporated (FACT-Hep and FAACT subdomains) to assess disease-specific symptoms. To date, 7 patients have been enrolled (Clinical Trial NCT05102721). Clinical trial information: NCT05102721 .

Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial

ObjectiveTo determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. MethodsThis multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. ResultsTwenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02–0.42), and this dose was selected as the MTD. ConclusionPaclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

Phase I Trial Combining Venetoclax with G-CSF, Cladribine, Cytarabine, and Mitoxantrone (CLAG-M) for Patients with High-Grade Myeloid Neoplasms

Background: Venetoclax in combination with hypomethylating agents or low dose cytarabine is a safe and effective treatment for newly diagnosed older, unfit patients with acute myeloid anemia (AML). Combining venetoclax with high intensity combination chemotherapy may increase response rates and eventual chance for cure. Previous studies have combined venetoclax with fludarabine, cytarabine, idarubicin, and G-CSF (FLAG-ida) with 89% of patients achieving a composite complete remission (CR), of which 93% were MRD negative (DiNardo et. al, AJH, 2022). We report the preliminary results of a phase 1 study examining the addition of venetoclax to a high intensity induction regimen, CLAG-M (cladribine, cytarabine, mitoxantrone, G-CSF), for fit patients with newly diagnosed adverse risk or relapsed/refractory high-grade myeloid neoplasms. Methods: Subjects with AML or other high-grade myeloid neoplasm (≥10% myeloid blasts in peripheral blood or marrow) were eligible if they had (1) new diagnosis with adverse risk disease by European LeukemiaNet 2017 criteria or (2) relapsed/refractory (R/R) disease. Venetoclax was administered on day 1-14 with a 4-day ramp-up. All patients received standard neutropenic prophylaxis and venetoclax was dose-adjusted for concomitant use of CYP3A4 inhibitors. Dose level (DL) is defined in Table 1. Dose limiting toxicity (DLT) was defined as grade &amp;gt;4 non-heme toxicity, prolonged aplasia &amp;gt; 49 days, or grade &amp;gt;3 non-heme toxicity lasting &amp;gt;48h and resulting in a treatment delay beyond day 56. Two subjects were started at DL 2 and a Bayesian optimal interval (BOIN) design was used for subsequent doses, with a true targeted DLT rate of 30%. Re-induction was allowed for persistent disease after the first cycle; subjects with CR were eligible to receive up to three cycles of venetoclax plus cladribine and cytarabine (CLAG) at the same dose level as induction. Target accrual is 20 subjects. Events were defined as death, relapse, or failure to achieve CR/CRi on post induction evaluation. The study was approved by the local IRB, and subjects were consented in accordance with the Declaration of Helsinki. Results: At time of data cutoff (7/6/23), 15 subjects (5 with newly diagnosed and 10 with R/R AML) were enrolled. Median age was 65 (range: 30-74) years. Five were newly diagnosed and 10 were R/R. Two subjects were enrolled at DL 1, 6 at DL 2, 5 at DL 3, and 2 at DL 4 as per the BOIN design. Two DLTs occurred: grade 4 respiratory failure at DL 2 and grade 5 sepsis at DL 3. Treatment related grade 3 adverse events (AE) included febrile neutropenia (5 subjects), dyspnea (2), mucositis (1), hypoxia (1), delirium (1), syncope (1), tumor lysis syndrome (1), and sepsis (1). Non-treatment related grade 3 AEs included hypokalemia (1 patient) and pericarditis (1). 28-day mortality was 7%. Twelve subjects received 1 cycle and 3 subjects received 2. Overall response rate (CR + CRi) was 73%. Two subjects achieved CR without MRD, 1 CR with MRD, 3 CRi without MRD, 5 CRi with MRD, 1 MLFS without MRD, 2 had persistent disease, and 1 died before evaluation. Median overall survival from treatment start was 7.4 months (95% CI 4.2 months - not reached [NR]). Median follow up of survivors was 6 months. Median event free survival was 3.3 months (95% CI 1.2 months - NR). Four subjects (1 newly diagnosed, 3 R/R) went on to receive allogeneic hematopoietic cell transplant (HCT). The administration of venetoclax presented challenges for inpatient and outpatient dosing, as medication diaries showed subjects underdosing venetoclax when taking concomitant posaconazole due to the complexity of the dosing regimen. Discussion: Preliminary results show that venetoclax can be safely added to a high intensity regimen for fit, high-risk patients without adversely affecting standard therapies including subsequent allogeneic HCT. Grade 3 and higher toxicity was common. In this preliminary analysis, the overall response rate was 73%, which is comparable to that observed with other chemotherapy regimens with the addition of venetoclax. A protocol amendment is in process to simplify venetoclax dosing with concomitant CYP3A4 inhibitors. This study will ultimately determine the MTD for subsequent phase II study to evaluate the therapeutic efficacy of venetoclax and CLAG-M.