Phase Ib Dose-escalation Study Research Articles

Neoadjuvant low-dose radiotherapy plus durvalumab and chemotherapy for potentially resectable stage III NSCLC: A phase Ib dose-escalation study

Background and purposeThis phase Ib study was designed to assess the safety/tolerability and preliminary antitumor activity of neoadjuvant low-dose radiotherapy (LDRT) plus durvalumab and chemotherapy for potentially resectable stage III non-small-cell lung cancer (NSCLC). Materials and MethodsEligible patients received dose-escalated radiotherapy (10 Gy in 5 fractions [cohort 1], 20 Gy in 10 fractions [cohort 2], and 30 Gy in 15 fractions [cohort 3]) according to a 3 + 3 design, with concurrent durvalumab plus standard chemotherapy for two cycles. Primary objective was safety/tolerability. Secondary objectives included major pathological response (MPR), pathological complete response (pCR), event-free survival (EFS), and exploratory biomarker analysis. ResultsNine patients were enrolled and completed the planned neoadjuvant therapy. No dose-limiting toxicity was recorded. Grade 3–4 treatment-related adverse events were observed in three (33.3 %) patients. Seven (77.8 %) patients successfully converted to resectable cases with R0 resection. No treatment-related surgical delay or death was reported. The MPR and pCR rates were both 33.3 % % (1/3) for cohort 1, 66.7 % (2/3) and 0.0 % for cohort 2, and 100.0 % (3/3), and 66.7 % (2/3) for cohort 3. At data cutoff, the 12 month-EFS rates were 33.3 %, 66.7 %, and 100 % for three cohorts, respectively. By biomarker analysis, TMB values were higher in either pathologically or radiologically responders than in others (all p > 0.05). ConclusionNeoadjuvant LDRT plus durvalumab and chemotherapy was well-tolerated in potentially resectable stage III NSCLC. The preliminary efficacy supports this combined regimen's potential, the optimal radiotherapy dosage was determined to be 30 Gy in 15 fractions, warranting further clinical investigation.

CPX-351 with Venetoclax in Patients with Relapsed/Refractory Acute Myeloid Leukemia: Results of a Phase Ib Study

Introduction: Relapsed/refractory acute myeloid leukemia (rAML) remains a significant challenge, with low response to therapy and poor long-term survival. Treatments focusing on achieving a response and, in eligible patients (pts), proceeding with an allogeneic stem cell transplantation (alloSCT) offer the best prospect for improved survival. CPX-351 is a liposomal fixed-ratio formulation of cytarabine and daunorubicin, which has demonstrated higher response rates and reduced early mortality in some subsets of AML and has also been shown to be active in rAML. The BCL2 inhibitor venetoclax (Ven) has demonstrated efficacy in AML in combination with other agents, such as hypomethylating agents, low dose cytarabine, and intensive chemotherapy. We conducted a Phase Ib/II dose-finding study to evaluate the combination of CPX-351 with Ven in AML. Herein we present the results of CPX-351 plus Ven in the cohort of rAML pts treated on study (NCT03629171). Methods: The study was designed with a safety lead-in phase to establish the safe dose and schedule in R/R AML, followed by 2 expansion cohorts to explore efficacy in (1) R/R AML and (2) frontline AML. Prior Ven use was allowed for pts with R/R AML. The dose of CPX-351 was fixed : daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 IV on days 1, 3 and 5 of induction, and daunorubicin 29 mg/m2 + cytarabine 65 mg/m IV on days 1 and 3 during consolidation. The starting effective dose of Ven was 300mg (at the -1 dose level) on D2-21 for the safety lead-in cohort with appropriate dose adjustment for concomitant CYP3A inhibitors. First, interruption of Ven after D14 was implemented if a D14 bone marrow was hypocellular and without evidence of leukemia. However, a second de-escalation was required (-2 dose level) with Ven given on day 2-8 of each cycle, and daunorubicin dose reduced to 22 mg/m2 during consolidation. This was found to be the recommended phase 2 dose. Results: Between 11/2018 to 1/2022, 33 pts were enrolled. The median age was 53 yrs (range, 26-72) and 61% were female. Diploid karyotype was present in 7 pts (21%), core binding factor rearrangements in 2 (6%), MECOM rearrangement in 2 (6%) and 13 (39%) had a complex karyotype. The most frequent mutations were DNMT3A (37%), TP53 (21%) and NRAS (21%). 8 (24%) pts had secondary AML including 4 (12%) with prior HMA exposure; the median number of prior lines of myeloid-directed therapies was 1 (1-7), including 58% of them with a previous exposure to Ven. Pts received a median of 1 cycle (1-4), and the median number of cycles to first response was 1 (1-2). The ORR was 45% (15/33), with 5 patient (15%) achieving CR, 8 (24%) achieving CRi and 2 (6%) achieving MLFS. The ORR was higher in those pts with only one prior line of therapy (59%) compared to those with 2 or more previous therapies (31%). The ORR for pts with prior exposure to Ven was 37% (7/19) vs 57% (8/14) for those not previously exposed to Ven (p=0.4). The 4- and 8-week mortality was 9 and 21%. 9/15 pts (60%) underwent alloSCT including 14 with CR/CRi/MLFS and 1 pt with an aplastic bone marrow insufficient for response assessment. The most frequent grade 3 or more adverse events were infections (45%, 30% of them pulmonary), febrile neutropenia (24%), and mucositis/stomatitis (6%). Three deaths occurred on study (2 due to sepsis and 1 due to cardiac arrest), all after one cycle of therapy. Other grade 3-4 events registered included rash (6%), cerebrovascular accident (6%), and intracranial hemorrhage (3%). After a median follow-up time of 20.7 months, the OS at 12 and 24 months was 34% and 25%, respectively. The median OS was 6.4 months. The EFS at 12 and 24 months was 26% and 19%, respectively. The median EFS was 2.8 months. For those who achieved response, the 2-year cumulative incidence of relapse and death without relapse were 41% and 28%, respectively. For those who underwent alloSCT, the median OS after alloSCT was 24 months, with 4 deaths after alloSCT, all following disease relapse. Conclusion: In this phase Ib dose escalation study, standard dose CPX-351 combined with 7 days of Ven was found to safe and tolerable in pts with rAML. The combination produced encouraging response rates in a poor risk population, including those with prior Ven treatment, allowing a significant proportion to undergo allo-SCT and extended survival. The RP2D is being studied in pts with newly diagnosed and less heavily pretreated AML.

Selective PI3Kδ Inhibitor Parsaclisib Combined with HDAC Inhibitor Chidamide in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma: Preliminary Results of a Phase Ib/Ⅱ Study

Background: Peripheral T-cell lymphoma (PTCL) is a highly heterogenous non-Hodgkin lymphoma with poor survival. Pts with relapsed/refractory PTCL (r/r PTCL) have extremely poor prognosis and limited treatment options. Conventional salvage treatments have a median progression-free survival (PFS) of only 3-4 months. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor has shown encouraging efficacy and favorable safety profile in B-cell malignancies. We developed a phase Ib/II study to evaluate the safety and efficacy of parsaclisib with HDAC inhibitor (HDACi) chidamide in r/r PTCL (NCT05083208). Here, we report the preliminary results of this study. Method: Eligible pts were ≤ 75 years old adults with histologically confirmed PTCL who received ≥ prior line of systemic therapy. Phase Ib dose-escalation study determined the maximum tolerated dose (MTD) of parsaclisib with chidamide using a 3 + 3 design. Parsaclisib was administered once daily at 3 dose levels (dose-level (DL) 1: 10 mg; DL2: 15 mg; DL3: 20mg) in the first 8 weeks followed by 2.5 mg QD in the subsequent treatment. Chidamide was administered at a fixed dose of 20 mg twice a week throughout the study. Once the MTD was established, pts were enrolled into phase 2 study to further characterize safety and efficacy. MTD of parsaclisib and objective response rate (ORR) were the primary endpoints; complete response rate (CRR), PFS, overall survival (OS) and tolerability were secondary endpoints. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) infection in the first 8 weeks were required. Results: From March 2022 to July 27, 2023 (date cut-off), 11 pts were recruited with a median age of 52 (39-74) years old. The median number of prior systemic therapies was 2 (1-5). Of 6 pts treated at DL1, 1 had dose-limiting toxicity (DLT) (grade 3 elevation of ALT/AST). No DLT was observed in 3 pts at DL2 and 2 at DL3. The DLT was resolved subsequently but the patient died from lymphoma progression. Treatment-emergent adverse events (TEAEs) were observed in all pts. The TEAEs were mainly hematologic toxicities and gastrointestinal reactions, most of which were grade 1/2. Grade 3/4 TEAEs were neutropenia (n=4), leukopenia (n=1), elevation of ALT/AST (n=1), and diarrhea (n=1) (Table 1). TEAE led to dose interruption in one patient. In 9 pts evaluable for responses (1 withdrew from this study and 1 was unevaluable), 5 (55.6%) pts achieved complete response (CR) and one (11.1%) partial response at the first efficacy assessment. In 7 pts previously exposed to chidamide, 4 pts achieved CR and 2 of them had a PFS > 16 months (Table 2 and Figure 1). Conclusion: Preliminary data demonstrated that selective PI3Kδ Inhibitor parsaclisib with HDACi chidamide was tolerable and produced promising responses in r/r PTCL, including patients previously exposed to chidamide. This trial is currently ongoing.

A phase 1b dose-escalation study of carfilzomib in combination with thalidomide and dexamethasone in patients with relapsed/refractory systemic immunoglobulin light chain amyloidosis

Introduction Proteasome inhibitors are the backbone of AL amyloidosis treatment – bortezomib being most widely used. Carfilzomib is a proteasome inhibitor licenced to treat multiple myeloma; autonomic and peripheral neuropathy are uncommon toxicities with carfilzomib. There is limited data on the use of carfilzomib in AL amyloidosis. Here, we report the results of a phase Ib dose-escalation study of Carfilzomib-Thalidomide-Dexamethasone (KTD) in relapsed/refractory AL amyloidosis. Results The trial registered 11 patients from 6 UK centres from September 2017 to January 2019; 10 patients received at least one dose of trial treatment. 80 adverse events were reported from 10 patients in the 1st three cycles. One patient experienced dose-limiting toxicity (acute kidney injury) at a dose of 45 mg/m2, and another patient had a SAR (fever). Five patients experienced an AE ≥ grade 3. There were no haematologic, infectious, or cardiac AE ≥ grade 3. The overall haematological response rate (ORR) at the end of three cycles of treatment was 60%. Conclusion Carfilzomib 45 mg/m2 weekly can be safely given with thalidomide and dexamethasone. The efficacy and tolerability profile appears comparable to other agents in relapsed AL amyloidosis. These data provide a framework for further studies of carfilzomib combinations in AL amyloidosis.

Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study

ObjectivesAnetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase...

A Phase Ib Study of the Safety and Efficacy of Venetoclax When Combined with Escalating Doses of Omacetaxine in Patients with Relapsed/Refractory Acute Myeloid Leukemia Failing Treatment with Venetoclax-Containing Regimens (VEN-OM)

Background: Venetoclax (VEN) combined with hypomethylating agents (HMA) are increasingly used as first line (1L) treatment in AML patients (pt) intolerant of intensive chemotherapy, due to the high complete remission (CR) rate (66.4%), tolerance of therapy and a median duration CR of 17.5 months. However, >60% of pts discontinued VEN/HMA (n=286) during the VIALE-A trial, mostly due to disease progression (DiNardo et al.N Engl J Med2020; 383:617-29). Outcomes for such pts receiving 2L and 3L therapies for relapsed/refractory (R/R) AML are poor and may be due to development of resistance to BCL-2 inhibition through mechanisms including the upregulation of the anti-apoptotic proteins BCL-XL or MCL1. In vitro studies demonstrate that VEN-resistant leukemia stem cells (LSC) are re-sensitized to BCL-2 inhibition when MCL-1 is also inhibited (Ramsey et al. Cancer Discov 2018; 8:1566-81). Novel MCL-1 inhibitors are thus in phase 1 clinical trials in R/R AML (e.g. NCT02675452), however there have been concerns for cardiotoxicity. Metabolic studies (Stevens et al. Nat Commun 2018: 9, 3694) indicate that the CD123+ malignant stem cell compartment of pts with high-grade MDS rely on upregulation of the protein synthesis machinery and mitochondrial oxidative phosphorylation (OxPhos). Omacetaxine (OM), a protein translation inhibitor both inhibits OxPhos and down-regulates (other) proteins with a short half-life such as MCL1. Treatment of a xenograft AML model with a combination of OM and VEN indicates in vivo synergistic effects in impairing mitochondrial respiration, ATP production, BCL-2 inhibition and MCL-1 downregulation (Fig 1A). We hypothesize this combination will prove effective in pts with R/R AML including those resistant to VEN-containing regimens. A similar drug combination is being studied by Dinardo et al. in R/R AML and MDS pts with RUNX1 mutations. Methods: VEN-OM is a single arm, open-label, phase Ib dose-escalation study in R/R AML pts (18-75y). The trial utilizes an innovative Bayesian Optimal Interval (BOIN) adaptive design (Yuan et al. Clin Cancer Res 2016)to determine the maximum tolerated dose (MTD), with a target dose-limiting toxicity (DLT) rate of 2%, and 4 pre-specified dose levels of OM, involving 24-30 pts. Major eligibility: ECOG 0-2, adequate organ function, R/R AML having progressed on ≥ 1L of therapy, which must have included a VEN-containing regimen. Exclusion criteria: Prior use of OM, peripheral blast count > 25 × 109/L, unresolved ≥ grade 2 clinically significant nonhematologic toxicities from prior anticancer therapy, unresolved ≥ grade 2 disseminated intravascular coagulation (DIC), other active malignancy within 1 year before study entry, or active infections. Induction Phase: Beginning with the first pt treated at the lowest dose of OM (0.625 mg/m2 q12h), OM dose escalation and de-escalation will involve comparison of the observed DLT rate at the current dose with a pair of fixed, pre-specified boundary rates. After a VEN ramp-up phase (days 1-3), the VEN dose is fixed at 400mg daily on days 4-28. OM doses are given days 1-7. OM dose will be escalated for each subsequent pt until the first DLT occurs, whereupon the current dose cohort is expanded to 3. In simulations of these conditions with a target DLT rate of 20%, the percentage correct selection of the MTD is between 60% with enrollment of 20 pts and 70% with 24 pts. Consolidation Phase: OM dose will be as per induction dose for days 1-7 of each cycle. VEN dose is 400mg days 1-21. Regimen comprises 3 cycles: Induction cycle x 1 and Consolidation cycles x 2 (Fig 1B). Primary endpoint is MTD of the combination of VEN and OM. Secondary endpoints include overall response rate after 3 cycles, characterization of adverse effects, and estimates of EFS and OS at 12 months. Exploratory objectives include measurement of validated markers of early renal injury including urine TIMP-2 x IGFBP7 and KIM-1 to identify pts susceptible to OM-induced nephrotoxicity and potential correlation with OM efficacy. Our previous experience with OM added to 7+3 ("AML-02", ASH 2022 abstract submitted) suggests that quantification of BM leukemia blast protein synthesis rates (Walker et al. Clin Cancer Res 2021, 27:819-30) and 'BH3 profiling' at presentation predicts outcomes, and these correlative studies will also be performed. The study recently opened, with the first patient completing induction without complications. Trial registered as (NCT04926285). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

743P A phase Ib dose escalation study of CD137 mAb agonist OC-001 as monotherapy in patients with advanced or metastatic cancer

OC-001 is a CD137 mAb agonist designed to show differential agonistic activity from that of competitor antibodies. OC-001 provided T cell activation that results in antitumor efficacy in humanized mouse tumor models in vivo.

A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors

BackgroundGlutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors.MethodsPatients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy.ResultsWe enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested.ConclusionThe combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors.Trial Registration ClinicalTrials.gov Identifier NCT03229278.

Phase Ib dose-escalation study of the hypoxia-modifier myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors

Abstract Objective Hypoxia is present in most solid tumors and acts as a driver of malignancy. Myo-inositol trispyrophosphate (ITPP) is a novel re-oxygenating compound without apparent toxicity. In preclinical models, it potentiates the efficacy of subsequent chemotherapy through vascular normalization. We sought to assess the safety, tolerability, and preliminary efficacy of ITPP. Methods In this monocentric, open-label, dose-escalation study following a 3+3 design, eligible patients with advanced primary and secondary hepatopancreatobiliary tumors received nine 8-h infusions of ITPP during 3 weeks across eight dose levels (1866–14,500 mg/m2/dose), followed by standard chemotherapy. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics and estimation of efficacy based on radiological responses and angiogenic serum markers. Registration number: NCT02528526. Results From April 2015 to July 2018, a total of 28 enrolled patients were assessed for the primary endpoints. ITPP was safe up to single doses of 12,390 mg/m2, and 32 ITPP-related adverse events occurred: 19 (67.8%) hypercalcemia, 5 (17.8%) hyponatremia, and 4 (14.2%) hypomagnesemia. Following ITPP monotherapy, 52% of patients displayed morphological disease stabilization. Following subsequent chemotherapy, 10% showed a partial response, and 60% had stable disease. Angiogenic markers were decreased in 60% after ITPP and tended to correlate with responses and survival after chemotherapy. Conclusion Administration of ITPP is safe up to 12,390 mg/m2 with favorable pharmacokinetics. Preliminary translational efficacy data show decreased angiogenic markers, which might indicate an anti-hypoxic effect and enhancement of chemotherapy through ITPP.

Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors

BackgroundThe combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab...

Allogeneic Hematopoietic Cell Transplantation Outcomes of Patients with R/R AML or Higher-Risk MDS Treated with the TIM-3 Inhibitor MBG453 (Sabatolimab) and Hypomethylating Agents

Allogeneic Hematopoietic Cell Transplantation Outcomes of Patients with R/R AML or Higher-Risk MDS Treated with the TIM-3 Inhibitor MBG453 (Sabatolimab) and Hypomethylating Agents

485P A phase Ib study of cetuximab combined with fruquintinib in the previously treated RAS/BRAF wild-type metastatic colorectal cancer: The preliminary result of CEFRU study

The standard third-line treatment of metastatic colorectal cancer (mCRC) is regorafenib, fruquintinib, or TAS-102. However, the efficacy was not satisfied. We conducted a phase Ib /Ⅱa clinical study to evaluate the safety and efficacy of fruquintinib plus cetuximab in mCRC（TPS151, 2021 ASCO GI） This time we reported the phase Ib dose-escalation study results.

564TiP A phase Ib dose-escalation study of ZN-c5, an oral selective estrogen receptor degrader (SERD), in combination with abemaciclib in patients with advanced estrogen receptor (ER)+/HER2- breast cancer

Hormone receptor+/HER2- breast cancer is the most common subset of breast cancer. Despite the availability of first-line endocrine therapy, one-third of patients diagnosed with early-stage disease experience disease recurrence. Resistance to endocrine therapy is a major clinical challenge. Although fulvestrant binds and degrades the ER and shows anti-tumor activity in this population, intramuscular injection is inconvenient, associated with injection-site reactions, and precludes achievement of higher and potentially more efficacious exposures.

562TiP A phase Ib dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian, peritoneal, or fallopian tube cancer

Ovarian, peritoneal, and fallopian tube cancer are deadly diseases with similar pathological and clinical features. Despite initial therapy with cytoreductive surgery and platinum-based therapy, many patients experience disease relapse either during (refractory) or within 6 months after (resistant) first-line platinum-based therapy. In these patients, various chemotherapies offer clinical activity but none is universally preferred. WEE1 tyrosine kinase is a critical component of G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of cyclin-dependent kinase 1 (CDK1). Inhibition of WEE1 leads to premature mitotic entry, DNA damage and apoptosis induction, and cell death. ZN-c3 is a novel, selective, and orally bioavailable WEE1 inhibitor that has demonstrated significant antitumor activity in nonclinical in vitro and in vivo models. A first-in-human study identified the maximum tolerated dose (MTD) of ZN-c3 when given as monotherapy. Combining ZN-c3 with chemotherapy may inhibit repair of chemotherapy-induced DNA damage and provide therapeutic benefit in this population. This phase 1b, open-label, multicenter study is evaluating the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of ZN-c3 in combination with pegylated liposomal doxorubicin, carboplatin, paclitaxel, or gemcitabine. The primary objectives are to determine MTDs and recommended phase 2 doses for each combination by a modified Bayesian continual reassessment method. Subjects are adult women with high-grade serous epithelial ovarian, peritoneal, or fallopian tube carcinoma who have received 1 or 2 prior chemotherapy regimens including platinum-based therapy and are refractory or resistant to platinum-based therapy. Study drug therapy is given in repeated 21- or 28-day cycles until disease progression or unacceptable toxicity. ZN-c3 is taken orally once daily. Chemotherapy is administered per protocol. Pharmacodynamic effects of therapy in tumor tissue and hair follicle samples will be explored. Subject recruitment is ongoing. NCT04516447 Zentalis Pharmaceuticals.

LBA-5 Phase Ib study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in patients with metastatic esophageal cancer

TIGIT (T-cell Immunoreceptor with Ig and ITIM domains) is a novel inhibitory immune checkpoint present on activated T cells and NK cells in multiple cancers, including esophageal cancer, and is often co-expressed with PD-1 on tumor infiltrating immune cells. Tiragolumab is a fully human IgG1/kappa monoclonal antibody that binds TIGIT to prevent its interaction with its ligand PVR (CD155). A phase Ib dose-escalation and dose-expansion study (GO30103, NCT02794571) showed that tiragolumab combined with atezolizumab was tolerable, and activity was seen in an expansion cohort of patients with PD-L1-positive non-small cell lung cancer (Bendell et al., 2020). We now report preliminary safety and anti-tumor activity of tiragolumab + atezolizumab in patients with metastatic esophageal cancer not previously treated with cancer immunotherapy. Patients enrolled in this phase Ib expansion cohort had metastatic esophageal cancer that had progressed on available therapies, had ECOG PS 0–1 and had not been treated previously with cancer immunotherapy. Patients were enrolled from the USA, EU, and Asia. PD-L1 expression was determined by central immunohistochemistry review. Patients received tiragolumab 400 mg or 600 mg IV every 3 weeks (Q3W) + atezolizumab 1200 mg IV Q3W until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. The safety, tolerability, and preliminary anti-tumor activity of tiragolumab + atezolizumab in patients with metastatic esophageal cancer not previously treated with cancer immunotherapy were evaluated at a data cut-off date of 8 April 2021. Twenty-one patients with metastatic esophageal cancers were treated (histopathological subtypes: squamous [13 patients], adenocarcinoma [7 patients] and neuroendocrine [1 patient]). Median age was 62 years; 5 patients (23.8%) had ECOG PS 0 and 16 patients (76.2%) had ECOG PS 1; 15 patients (71.4%) had received ≥2 prior therapies; 7 patients (33.3%) were from Asia and 14 patients (66.7%) were from US/EU. Treatment-related AEs (TRAEs), as assessed by investigators, occurred in 14 patients (66.7%), with a Grade 3 TRAE seen in 1 patient. Immune-mediated AEs (imAEs) occurred in 12 patients (57.1%). No Grade 4 or 5 TRAEs or imAEs were observed. The most common AEs reported (in ≥15% of patients) were malignant neoplasm progression (28.6%), anemia (23.8%), decreased appetite, cough, aspartate aminotransferase increase, amylase increase (all 19.0%). Of 18 evaluable patients with at least one tumor assessment, there were 5 partial responses (objective response rate of 27.8%). The disease control rate was 50%, with 1 patient still in the study at 2+ years. Tiragolumab combined with atezolizumab was well-tolerated with an acceptable safety profile, and showed preliminary antitumor activity in heavily pretreated patients with metastatic esophageal cancers not previously treated with cancer immunotherapy.

Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors

Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.

185TiP A phase Ib dose-escalation study evaluating trastuzumab deruxtecan (T-DXd) and durvalumab in combination with chemotherapy as first-line treatment in patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and HER2 overexpression (DESTINY-Lung03)

Background: In patients (pts) with metastatic NSCLC without EGFR/ALK/ROS1 genomic aberrations, platinum doublet chemotherapy (ctx) + anti–PD-1/L1 immunotherapy is the current first-line standard of care. HER2 overexpression, an established target for treatments in breast and gastric cancers, is observed in up to 30% of pts with NSCLC. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload.

BOLD-100-001 (TRIO039): A phase Ib dose-escalation study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastrointestinal solid tumors.

TPS145 Background: Although most cancers are initially susceptible to existing anticancer therapies, over time cancer cells develop resistance. BOLD-100 is a first-in-class therapy that targets the GRP78 pathway, a major regulator of cellular stress and resistance. This therapy suppresses drug resistance, survival and proliferation by restraining stress-induced upregulation of GRP78 in tumor cells, leading to inhibition of the cell survival response. BOLD-100 successfully completed a Phase 1 monotherapy trial, with a manageable safety profile; it has demonstrated synergy in established preclinical models in combination with a wide variety of anticancer therapies and shown to restore sensitivity of drug-resistant cell lines. Methods: BOLD-100-001 is a multicenter, prospective, two-stage, non-randomized Phase 1b dose escalation and expansion study of BOLD-100 in combination with FOLFOX chemotherapy for selected advanced solid gastrointestinal (GI) tumors: colorectal (CRC), pancreatic (PANC), gastric (GC) and bile duct cancers (BDC). Each patient will receive BOLD-100 along with FOLFOX chemotherapy on Day 1 of each 14-day cycle. In the dose-escalation phase (Part A), patients will be enrolled to determine the combination recommended dose using a standard 3+3 design. In the dose-expansion phase (Part B), up to 80 patients with selected GI tumors will be enrolled in 5 cohorts (comprising the 4 GI cancers referred) and treated with BOLD-100 at the recommended dose and FOLFOX, until progressive disease or unacceptable toxicity. In Part A dose-escalation, the primary objective is to assess the safety, tolerability and maximum tolerated dose. The Part B dose-expansion will assess the efficacy (progression free survival, overall survival and response rate), of FOLFOX chemotherapy plus BOLD-100. Secondary objectives in Part A and B include the assessment of pharmacokinetic and pharmacodynamic parameters and potential biomarkers predictive of efficacy. Eligible patients will have previously treated histologically/cytologically confirmed metastatic/unresectable GI tumor (CRC, PANC, GC or BDC), measurable disease per RECIST criteria, an ECOG performance score of 0 or 1, and adequate organ function. In Part A, no formal statistical hypotheses will be tested; analysis of the data will focus on comparisons of safety and dose-limiting toxicities between cohorts and only descriptive methods will be used. In Part B, Bayesian modelling will be used to continually reassess the efficacy endpoints: progression free survival, overall survival and objective response rates. The study was opened for enrollment in August 2020; approximately 25-30 patients will be screened to achieve up to 20 patients in Part A and up to 80 patients will be enrolled in Part B with a maximum of 25 patients per arm. Clinical trial information: NCT04421820.

Results of the Phase 1b Dose Escalation Study of OPB-111077, Decitabine, and Venetoclax for the Treatment of Newly Diagnosed or Relapsed/Refractory AML

Background: The combination of a hypomethylating agent (HMA) and the Bcl-2 inhibitor venetoclax (VEN) has revolutionized the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML). However, patients treated with this regimen inevitably relapse and subsequent treatment options are limited. Furthermore, the success of this combination in the relapsed/refractory setting has been less impressive. Mechanisms of resistance to HMA/VEN are of great interest, and alterations in leukemic cell metabolism have been implicated. It is hypothesized that drugs that target oxidative phosphorylation (OXPHOS), fatty acid metabolism, and /or amino acid metabolism may be successful in overcoming HMA/VEN resistance. OPB-111077 is a novel, oral, low-molecular-weight compound that was shown in preclinical models to inhibit mitochondrial electron transport and have an inhibitory effect on the growth of AML cells. When given in combination with decitabine, OPB-111077 showed a more potent antitumor effect in a KG-1 tumor-bearing mouse model, thus providing support for conducting clinical trials of this combination. AML cells treated with OPB-111077 and venetoclax have also been shown to have decreased proliferation and increased apoptosis. The effects on proliferation and apoptosis of the combination of OPB-111077 and venetoclax were more pronounced in AML cells that were genetically engineered to increase OXPHOS. These data formed the basis for the development of a clinical trial utilizing the triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML. Herein, we report results from the Phase Ib dose escalation study. Methods: In this phase Ib single center study (NCT03063944), OPB-111077 is administered daily starting on day 1 and continuing throughout the treatment cycle. Decitabine 20mg/m2 is given for 5 days starting on day 4 of cycle 1. Venetoclax 70mg daily (if receiving posaconazole prophylaxis) or 100mg daily (if receiving voriconazole) is started on day 4 and given continuously until day 28. If a response is seen within 2 cycles, treatment continues until toxicity, disease progression, or availability of an alternative therapy. Patients were enrolled in cohorts of escalating dose levels of OPB-111077 using a traditional 3+3 design. The primary objectives were to determine preliminary safety and tolerability as well as maximum tolerated dose (MTD) of OPB-111077. The secondary objective was to measure preliminary efficacy. Correlative studies including metabolomics, ATP measurement, apoptosis, and proliferative assays were performed on samples of blasts and non-cancerous cells that were collected from blood or marrow. Results: As of July 15, 2020, 2 patients with newly diagnosed AML and 7 patients with relapsed/refractory AML were treated with the triplet. Patients received OPB-111077 at 150mg (n=3), 200mg (n=3), and 250mg (n=3). Median age was 73 years (range, 23-79) and 7 patients (78%) were male. The median number of prior systemic anticancer regimens for patients with relapsed/refractory disease was 2 (range, 1-5); no patients had undergone prior stem cell transplant. The median treatment duration has not yet been reached; 3 patients are receiving ongoing treatment. No patients experienced a dose limiting toxicity. The most common Grade ≥3 adverse event (AE) was febrile neutropenia (56%). No patients discontinued due to AEs. No pts experienced tumor lysis syndrome. Three patients died after completing their study treatment, all due to progressive AML. The best overall response to therapy was a complete remission in 2 (22%) patients (1 with newly diagnosed AML and 1 with relapsed/refractory disease). Metabolomics using liquid chromatography/mass spectrometry was performed on paired pre- and post-treatment samples and intracellular metabolic changes in glycolysis and the tricarboxylic acid (TCA) cycle were observed consistent with on-target effects. Conclusion: The triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML was safe and well tolerated, and showed preliminary anti-leukemic efficacy. A planned expansion phase is underway utilizing the 250mg daily dose of OPB-111077. Disclosures Martinez-Outschoorn: Otsuka Pharmaceutical: Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Kasner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical: Research Funding.

1026MO Phase Ib dose escalation study of novel immunogenic cell death (ICD) inducer PT-112 plus PD-L1 inhibitor avelumab in solid tumours

1026MO Phase Ib dose escalation study of novel immunogenic cell death (ICD) inducer PT-112 plus PD-L1 inhibitor avelumab in solid tumours