Dose-limiting Hematologic Toxicity Research Articles

Sarcopenia as a Predictive Factor for Carboplatin Toxicity in Patients with Advanced Non-Small Cell Lung Cancer

Sarcopenia in cancer patients often negatively impacts various outcomes. Carboplatin, a first-line chemotherapy for non-small cell lung cancer (NSCLC), is dosed based on body weight, which doesn’t account for sarcopenia. This study evaluated the association between sarcopenia and carboplatin-related toxicity in NSCLC patients. Patients with locally advanced or metastatic NSCLC treated with carboplatin were included. Toxicity events during the first two cycles of treatment were recorded. Sarcopenia was assessed using pretreatment computed tomography scans analyzed with Slice-O-Matic V4.2 software, defining sarcopenia as a skeletal muscle index (SMI) of <52.4 cm2/m2 for men and <38.5 cm2/m2 for women. Among 146 patients, 52% had sarcopenia. Hematological toxicity occurred in 71.2% of all patients and 77.6% of those with sarcopenia. The fat-free mass index (FFMI) was independently associated with hematological toxicity and dose-limiting toxicity (DLT), which was observed in 55.5% of patients. Sarcopenia significantly correlates with hematological toxicity and DLT during carboplatin treatment in NSCLC patients. Given its prevalence and noninvasive detection, further research is needed to understand its impact on treatment outcomes.

The vedotin antibody-drug conjugate payload drives platform-based nonclinical safety and pharmacokinetic profiles.

Nonclinical safety and pharmacokinetic data for MMAE and 14 vedotin ADCs were evaluated to determine patterns of toxicity, consistency of pharmacokinetic results, and species differences between rats and monkeys. Most nonclinical toxicities were antigen-independent, common across ADCs, and included hematologic, lymphoid, and reproductive toxicity related to MMAE pharmacology. Hematologic toxicity was the dose-limiting or predominant toxicity for the majority of vedotin ADCs in both species. Tissue expression of the targeted antigen of an ADC rarely correlated with dose-limiting toxicity (DLT); only two ADCs had antigen-dependent skin DLTs. For two additional ADCs, antigen-dependent delivery of MMAE in the bone marrow may have exacerbated the antigen-independent hematologic DLT. The highest tolerated doses and pharmacokinetics were similar within a given species, with rats tolerating higher doses than monkeys. Studies longer than one month in duration detected the same or fewer toxicities than one-month studies and had no additional findings that affected the human risk assessment. These data support opportunities to streamline ADC toxicity assessments without compromising human starting dose selection or target organ identification.

A phase I study of irinotecan combined with BAY1895344 (ATR inhibitor) in advanced solid tumors: Results of ETCTN 10402 dose escalation.

3077 Background: ATR protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA defects in various cancers. The topoisomerase-I (Top1) inhibitor irinotecan induces DNA damage. The ATR inhibitor BAY1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and GI cancer xenografts when combined with Top1 inhibitors . Methods: This phase Ia trial assessed elimusertib in combination with irinotecan in adult patients with refractory advanced solid tumors for whom irinotecan can be considered standard care. Patients with previous irinotecan exposure were excluded. Two dosing schedules were used: 1) Biweekly - irinotecan IV (starting at 150 mg/m2) D1 + elimusertib (starting dose 20 mg PO BID) D1,D2 (cycle=14 days); 2) Weekly - irinotecan (starting at 50 mg/m2) IV on D1,8,15 with elimusertib (starting at 20 mg PO daily) on D2,D3,D9,D10 and D16,D17 (cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity. Results: A total of 21 patients were enrolled in dose escalation (N=9 [Biweekly] and N=12 [Weekly], median age 58 and 2 lines of prior therapy. For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized (Table 1). The majority of evaluable patients in both schedules had initial disease control (56% [biweekly] and 67% [weekly]). One confirmed partial response was seen in the biweekly RP2D. Median progression-free survival was 2.1 mo [biweekly] and 2.5 mo [weekly]. PK results will be presented at time of meeting. Conclusions: Both RP2D and MTD of elimusertib in combination with irinotecan were reached for both dosing schedules: irinotecan 150 mg/m2 IV D1 + elimusertib 10 mg BID PO D1,D2 (biweekly) and irinotecan 25 mg/m2 IV on D1 + elimusertib (20 mg PO daily) on D2,D3 (weekly). Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansion but the concept of ATR + topo I combination remains scientifically relevant. Clinical trial information: NCT04514497 . [Table: see text]

Abstract CT120: Phase 1 trial of bortezomib and clofarabine combination in adults with refractory solid tumors

Abstract Background/Rationale: The combination of the proteosome inhibitor bortezomib (B) and purine analog clofarabine (C) induced synergy in the NCI-ALMANAC screen of FDA-approved cancer drug combinations; preclinical xenograft studies confirmed this activity and suggested a combination mechanism of action involving greater-than-additive effects on markers of DNA damage response (DDR) and pyroptotic cell death. We conducted a phase 1 clinical trial (NCT02211755) to assess the safety of the B and C combination in patients (pts) with solid tumors and myelodysplastic syndrome (MDS), and to determine the effect of the combination on biomarkers of cell death and DDR. Due to limited MDS pt accrual, this cohort was terminated early, and MDS pt data are not included here.Objectives: The primary objective was to assess safety and maximum tolerated dose (MTD) of B and C in pts with solid tumors and MDS. Secondary objectives were to assess pharmacodynamic (PD) effects using validated assays for cell death and DDR in tumor biopsy tissue and circulating tumor cells (CTCs).Design: The dose escalation followed a 3+3 design, enrolling at least 1 pt from each group (solid tumor and MDS) per dose level until hematologic dose-limiting toxicity (DLT) was observed. Adverse events (AEs) were graded using CTCAE v4.0. Ten planned dose levels (DL) included C ranging from 1 to 10 mg/m2 on D2-5 of cycle 1 and D1-5 from cycle 2 on and B from 0.8 to 1.5 mg/m2 on D1 and D4 of 21-day cycles. Response was assessed by RECIST 1.1 every 2 cycles. Biopsies were performed on the expansion cohort pre-dose, 2-4 hours after C on C1D1, and C2D4; CTCs were collected pre-dose, C1D2, day 1 of subsequent cycles, and at progression.Results: We enrolled 25 pts with advanced solid tumors (15 male, 10 female). Median age was 62 years (range 30-81). DLT occurred in 4 pts (at DL3 [1 pt], DL5 [2], and DL4 [1]) and included Grade 4 neutropenia (3), Grade 3-4 thrombocytopenia (3), and Grade 3 anemia (1). There were no Grade 5 AEs. DL4 (B 1.3 mg/m2 D1 and 4, C 1.5 mg/m2 D1-5, 21-day cycles) was the MTD. Twenty-one pts were evaluable for response; the best response was stable disease (SD) for 10 pts (47.6%). Median duration of response for pts achieving SD was 3.5 months (range 2-7). Of note, 3 out of the 10 colorectal cancer (CRC) pts had SD &amp;gt; 4 months. Four pts with CRC have been enrolled in an expansion cohort for biomarker evaluation; induction of pyroptosis has been measured in a limited number of paired biopsies collected to date. Conclusions: Despite preclinical evidence of synergy, the human equivalent of the efficacious preclinical combination dose could not be achieved clinically, which may account for the lack of antitumor response. Prolonged SD was observed in 3 pts with CRC. PD analyses, including of CTCs and additional cell death biomarkers, are ongoing. Funded by NCI Contract No. HHSN261201500003I. Citation Format: Andre L. De Souza, Naoko Takebe, Alice P. Chen, James H. Doroshow, Ralph E. Parchment, Apurva K. Srivastava, Lawrence Rubistein, Deborah Wilsker, Brandon L. Miller, Murielle Hogu, Geraldine O`Sullivan Coney, Shivaani Kummar, Jeevan Govindharajulu, Robert Meehan, William G. Herrick, Angie Dull, Donna Ketchum, Shaowei Li, Jiuping Ji, Richard Piekarz. Phase 1 trial of bortezomib and clofarabine combination in adults with refractory solid tumors [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 CT120.

Venetoclax in Combination with Intermediate Doses of Cytarabine in Consolidation Phase for Acute Myeloid Leukemia Patients in First Complete Remission; Results of the Part 1 of the Phase 1/2 Multicentric Covenidac Study

For authors: Please: L Gastaud and P Peterlin: co-primary, H dombret et C Recher: co-last Background: The French ALFA-FILO AML intergroup launched the BIG-1 trial (EudraCT No.: 2014-000699-24) in 2015 to evaluate different intensive chemotherapy (ICT) strategies aiming at improving the survival of younger adults with acute myeloid leukemia (AML). All patients (pts) with previously untreated non-APL and non-CBF AML aged 18-60 years were eligible for this trial. The trial design included several randomization types. Results of the R1 and R2 randomizations, namely idarubicin vs daunorubicin for induction and IDAC vs HDAC for consolidation, will be reported at this meeting. In patients who achieved first complete remission (CR), randomizations R4 consisted of nested randomized Phase 2 or 1/2 studies evaluating the addition of new drugs to the IDAC/HDAC consolidation cycles. The protocol was designed to allow several sequential multicenter R4 evaluations of various new agents over the trial period. Venetoclax (VEN) has proved its efficacy when combined to azacitidine or low dose cytarabine in unfit AML pts (DiNardo et al. 2020; Wei et al. Blood 2020). Its role in fit patients treated with ICT is still under investigation. The COVENIDAC Phase 1/2 R4 sub-study is evaluating the safety and efficacy of VEN added to IDAC during the consolidation cycles of CR pts. We report herein the result of the Phase 1 part. Methods: The primary objective of this Phase 1 study was to determine the maximum tolerated dose (MTD) of VEN in combination with IDAC during the consolidation cycles, which will be the recommended dose for the Phase 2 (RP2D). Dose limiting toxicities (DLTs) were assessed during the first cycle of consolidation (C1) according to a 3+3 design. A maximum of 3 consolidation cycles was planned depending on the AML risk group. Hematological DLT was defined as no peripheral blood count recovery within 56 days from day 1 of the cycle. Non-hematological DLTs were defined as Grade ≥4 toxicities or Grade ≤3 toxicities which have not recovery by day 56 and deemed related to VEN per investigator opinion. VEN was started at dose level (DL) 1: 100 mg/d from day 1 to 8. In the absence of DLTs at DL1, 3 others DL were planned: 200 mg/d from day 1 to 8 (DL2); 400 mg/d from day 1 to 8 (DL3), and 400 mg/d from day 1 to 14 (DL4). IDAC was administrated at 1.5 gr/m² twice daily on day 1/3/5 for DL1, DL2 and DL3 pts, then on day 1/2/3 for DL4 pts after a protocol amendment. Main inclusion criteria were: pts in first CR following 1 or 2 courses of induction chemotherapy fit for further ICT; favorable and intermediate risk AML as defined by the protocol; ECOG PS ≤2; written informed consent. Measurable residual disease (MRD) was assessed by multiparametric flow cytometry (MFC) in all pts as well as NPM1-qPCR in NPM1-mutated pts. Results: Between 06/2021 and 04/2022, 15 pts from 9 centers were screened and enrolled. Pt characteristics were as follows: median age, 42 years (IQR, 30-49); 2 males/7 females; ECOG-PS, 0 in 10 pts and 1 in 5 pts; favorable/intermediate/adverse ELN-2017 risk, 9/2/4. Neutropenia and thrombocytopenia durations are shown in Table 1. Only 1 hematological DLT was observed at DL3 (platelet count of 96 giga/L at day 56 in a patient who was infected by Covid-19). Overall, there were very few non hematological AEs ( Table 2, no grade 4) and only 4 SAEs (1 related to IDAC/VEN during C1, 3 non-related). No non-hematological DLT was observed. No patient died during the DLT observation period, 1 experienced a septic shock (C2, DL2). One pt received only C1 (due to DLT), 7 received 2 cycles, and 7 received 3 cycles. Median time between initiation of subsequent consolidation cycles was 37.5 days (IQR, 35-41) for C1/C2 and 40 days (IQR, 35-43) for C2/C3. One pt had to stop VEN during C3. Six pts received an allogeneic HSCT (5 in CR1, 1 after salvage). With a median follow-up of 13.5 months, 3 pts relapsed and 2 died. MRD results will be presented. Conclusion: VEN/IDAC combination appears to be feasible and safe as consolidation therapy, with expected thrombocytopenia and neutropenia durations. These durations appeared even shorter at DL4, when IDAC was given on 3 consecutive days. VEN at 400 mg/d from day 1 to 14 combined with IDAC on day 1/2/3 was thus retained as RP2D for the randomized Phase 2 with RFS as primary endpoint. This phase 2 has already recruited 29 of the 200 pts planned.

Beat AML S8 Group 2: Gilteritinib (GILT) in Combination with Decitabine (DEC) and Venetoclax (VEN) in Untreated FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Age ≥60 with High and Low Variant Allele Frequency (VAF)

Background: GILT is a potent oral selective FLT3 kinase inhibitor ( FLT3i) approved for the treatment of patients with relapsed/refractory FLT3 mutated ( FLT3m) AML. However, the optimal combination in older, newly diagnosed (ND) FLT3m AML patients is unknown. GILT in combination with azacitidine (AZA) had higher initial response rates, but did not improve overall survival (OS), compared to placebo in the LACEWING trial (Wang et al. Blood 2021). GILT followed by decitabine (DEC) was also tested and found to be safe, but the efficacy did not meet pre-determined criteria (NCT03013998, S8 Group 1). In the interim, VEN + AZA/DEC emerged as the new standard of care for older/unfit patients with AML (DiNardo et al. NEJM 2020). Thus, the Beat AML S8 study was amended to assess the safety and efficacy of GILT in combination with DEC and VEN in newly diagnosed FLT3m AML patients aged ≥60 years (NCT03013998, S8 Group 2). Methods: The S8 Group 2 sub-study was part of the multicenter (15 sites) Beat AML Master Trial. Key eligibility criteria included ND FLT3m AML patients aged ≥60 years who are not able to receive intensive induction chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. A conventional 3+3 design was used to determine the recommended phase 2 dose (RP2D) of GILT+DEC+VEN. Patients were treated with GILT at three dose levels (DL). During induction, treatment consisted of GILT 120mg/day on days 1-7 then 80mg/day on days 8-28 for dose level 1 (DL1), or on days 8-21 (DL-1), or on days 8-14 (DL-2). All patients received DEC at 20mg/m 2 on days 8-12, and VEN at 400mg/day (or at 100mg/day if concomitant antifungal) on days 8-28. Patients who achieved a complete remission (CR) or CR with hematologic improvement (CRh) received GILT 80mg/day on days 1-15 (DL1) or days 1-7 (DL-1, DL-2), DEC on days 1-5 (All DLs), and VEN on days 1-15 (DL1, DL-1) or days 1-10 (DL-2) for an additional 12 consolidation cycles. The primary end point was to determine the tolerability and toxicity of GILT in combination with DEC and VEN. Secondary end point was the composite CR (CRc: CR/CRh) rate. Response was assessed using modified 2017 European LeukemiaNet (ELN) AML criteria. Results: Between 10/22/2020 and 6/13/2022, 19 patients were consented, of whom 18 started treatment and were included in the analysis. The median age was 73 and baseline patient characteristics are shown in Table 1. The first 2 patients treated at DL1 both experienced hematologic dose-limiting toxicities (DLTs) with persistently low absolute neutrophil count (ANC). Therefore, the GILT dose was de-escalated to DL-1, where 8 patients were enrolled and treated. Among the 6 evaluable patients on DL-1, DLTs occurred in 2 patients; one had hematologic DLT and the other had failure to thrive. This led to dose de-escalation to DL-2. In DL-2, 2/8 patients experienced hematologic DLTs. The protocol was then amended to include DL-3 and DL-4, but the trial was closed by the sponsor due to priority transition and enrollment was halted so further dose reductions were not evaluated. Adverse events (AEs) were mostly hematologic, and 11 patients had treatment-related adverse events (TAEs), 10 of them grade 3 or higher. Median (range) time on treatment was 6 (1-25) cycles. Most common reason for treatment discontinuation were adverse event (3, 21.4%), recurrence (2, 14.3%), stem cell transplant (2, 14.3%), and death (2, 14.3%) Nine patients achieved CR, 2 patients achieved CRh and 1 patient achieved complete remission with incomplete hematologic recovery (CRi). The CRc rate (CR/CRh) was 61.1% (11/18, 95% CI: 38.6%-83.6%). After a median follow up of 19.7 months, the median overall survival and duration of response were not reached. One-year overall survival (OS) was 71.8% (95% CI: 44.9-87.2). Conclusion: Triplet therapy of GILT+DEC+VEN inND FLT3m AML patients ≥60 years old induced a high response rate (CRc rate 61.1%), and the median OS was not reached at time of this report (median follow-up 19.7 months). The typical dose of GILT 120mg/day with DEC+VEN was associated with significant hematology toxicities, which required multiple dose level reductions. At the reduced dose (GILT 80mg/day on days 1-7), the combination therapy was generally safe and well tolerated. A Phase 2 clinical trial sponsored by Astellas of GILT+AZA+VEN as frontline treatment for ND older patients with FLT3m AML is now enrolling (NCT05520567). Funding: this study was funded by Astellas Pharma Inc.

Results of a Phase 1 Trial Testing the Novel Combination Therapy of Venetoclax and Ruxolitinib in Relapsed/Refractory Acute Myeloid Leukemia Patients

Introduction : A functional small molecule screen on a large cohort of primary AML patient samples revealed that the combination of Ruxolitinib (Rux) and Venetoclax (Ven) exhibited ex vivo efficacy and synergy in both newly diagnosed and R/R AML. This observation motivated a Phase I multi-center trial to evaluate Rux+Ven in R/R AML, for which we now report complete toxicity and efficacy data for 30 subjects. Methods: This study was designed to identify a maximum tolerated or recommended Phase II dose (RP2D) and evaluate the overall safety and preliminary efficacy of Rux+Ven therapy. Eligible subjects were ≥18 years old with R/R AML. There was no restriction on the number of previous therapies or prior exposure to Ven or Rux. We included subjects with prior allogeneic transplant if GVHD was controlled and prior MDS (≥75 years old or having poor cardiac or kidney function) who progressed on a hypomethylating agent (HMA) but had no primary AML therapy. In cohorts of 3 to 4, subjects were assigned to receive Rux+Ven at 1 of 6 dose levels according to the “keyboard” Bayesian toxicity probability interval design applied to a target dose-limiting toxicity (DLT) rate of 30%. DLTs were defined as non-disease-related, Grade ≥3 non-hematologic toxicities, with exceptions for nausea, vomiting, infections, febrile neutropenia episodes, and electrolyte abnormalities that resolved within 48 hours. Hematologic DLT was specified as Grade 4 neutropenia after 42 days in the absence of disease. The DLT evaluation period covered the first cycle. Subjects could continue study therapy after two 28-day cycles if they had a response (ie, CR/CRi or MLFS) or were otherwise deriving clinical benefit. Results : This Phase 1 study has completed enrollment (n=30), with all but one patient off-treatment as of June 2023. Baseline patient characteristics are summarized in Table 1. Median age was 69 (range 29-84), 40% of subjects had ≥3 prior therapies, and 43% had prior Ven. At enrollment, 30% had prior MDS, 24% had mutated TP53 (of 25 patients with available data), and 47% had CD56+ blasts. The numbers of patients treated by dose level (DL) were: 3 on DL0 (200 mg qd Ven; 10 mg bid Rux), 4 on DL1 (400 mg qd Ven; 10 mg bid Rux), 3 on DL2 (400 mg qd Ven; 20 mg bid Rux), and 20 on DL3 (400 mg qd Ven; 30 mg bid Rux), the highest dose level of the study. Per prescribing guidelines, the cycle 1 Rux doses of 15 subjects and Ven doses of 20 subjects were reduced because of a concomitant CYP3A inhibitor. The regimen was well-tolerated. As no DLTs were observed, DL3 is the RP2D. The median (interquartile range) duration of therapy was 55 (36-93) days. The most common grade ≥3 hematologic AEs, regardless of attribution, were thrombocytopenia (50%; which was 30% at study enrollment), anemia (40%; 40% at enrollment), neutropenia (37%; 10% at enrollment), febrile neutropenia (33%), and leukopenia (33%; 7% at enrollment). Six subjects had a Grade 5 AE: 4 were unrelated to study drug (2 death NOS, 1 lung infection, 1 respiratory failure) and 2 were potentially related to Ven (1 sepsis, 1 neutropenic pneumonia). Over the first 2 cycles of study therapy, the Clinical Benefit Rate (CBR; defined as the proportion of subjects obtaining at least stable disease) was 63% (95% CI: 44%-80%). Morphologic leukemia-free state (MLFS) was achieved in 20% (95% CI: 8%-39%) and Composite Complete Remission in 10% (95% CI: 2%-27%). Median overall survival (OS) was 3.7 months (95% CI: 2.3-6.5), with 23% (95% CI: 10%-39%) alive 1 year after commencing Rux+Ven. Two participants were exceptional responders: the first achieving MLFS and receiving 16 cycles of study therapy and the second having a complete remission and remaining on-treatment after 31 cycles. Pre-Rux+Ven CD56 expression on blasts correlated with worse response (all 6 ≥MLFS patients were CD56-; Fig 1) and overall survival (HR=2.37, p=0.044; Table 1). Correlative studies such as ex vivo drug assessment, genomic analysis, CyTOF, and single-cell imaging will be presented to enhance this finding. Conclusion: The novel, all-oral combination of Rux+Ven in R/R AML patients was well-tolerated with no DLTs and an encouraging 63% CBR over cycles 1-2. Negative CD56 was a biomarker of response, although additional work is required to determine if this is a broad association with Ven-based therapies or unique to the Rux+Ven combination. The tolerable toxicity profile of Rux+Ven makes it a promising combination to test with HMAs in high-risk AML patients.

Preliminary Safety and Efficacy of Venetoclax and Selinexor in Combination with Chemotherapy in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia: Selclax

Background: Survival rates for children and adolescent/young adults (AYAs) with relapsed or refractory acute myeloid leukemia (R/R AML) remain poor. Previous clinical trials have demonstrated that the selective inhibitor of nuclear export selinexor and the BCL2 inhibitor venetoclax are each safe and active when combined with chemotherapy in children with R/R AML (NCT02212561, NCT03194932). However, many patients are refractory to these combinations. Preclinical data indicate that selinexor and venetoclax are synergistic and that selinexor may abrogate resistance to venetoclax. We thus aimed to characterize the toxicity profile and explore preliminary activity of venetoclax and selinexor with chemotherapy in pediatric and AYA patients with R/R AML and report results from the dose escalation phase of the SELCLAX clinical trial (NCT04898894). Methods: SELCLAX is a Phase I and expansion cohort study of selinexor and venetoclax in combination with chemotherapy in pediatric and AYA patients with R/R AML. For the dose escalation phase, eligibility criteria included &amp;lt; 30 years of age, adequate organ function and performance status, primary refractory, early first relapse (&amp;lt; 12 months from initial diagnosis), relapsed and refractory to salvage, post-transplant relapse or second or greater relapse AML or acute leukemia of ambiguous lineage (ALAL). The primary endpoint was determination of the recommended phase 2 dose (RP2D) of venetoclax and selinexor with chemotherapy. In the dose level 1 (DL1) cohort, venetoclax was given at 360 mg/m 2 per dose (max 600 mg) on days 1-21 in combination with selinexor at 40 mg/m 2 on days 1, 8, 15. For dose level 2 (DL2), venetoclax was dosed as in DL1, and selinexor was dosed at 40 mg/m 2 twice weekly on days 1, 3, 8, 10, 15, 17. Chemotherapy (fludarabine 30 mg/m 2, cytarabine 2 g/m 2 ± granulocyte colony stimulating factor 5 mcg/kg [FLA(G)]) was given on days 16-20. Response was evaluated by blast percentage in day 8 and 15 peripheral blood and in day 15 and end-cycle bone marrow. Any patient with a two-log (100-fold) reduction in measurable residual disease (MRD) between baseline and Day 15 was designated an “exceptional responder” (ER). At the discretion of the treating physician, ER patients could continue venetoclax until day 28 with additional selinexor (DL1: day 22; DL2: day 22, 24); FLA(G) could either be omitted or given on days 30-34; omission of FLA(G) deemed a patient non-evaluable (NE) for dose-limiting toxicity (DLT). Evaluable patients were assessed for DLTs, and dosing was escalated according to a rolling-six design. Results: As of July 14, 2023, fifteen patients (aged 3-17 years) with R/R AML (n=14) or ALAL (n=1) were enrolled in the dose escalation phase ( Table 1). Nearly all patients had high-risk cytomolecular features: KMT2A-rearranged (n=5), NUP98-rearranged (n=5), -7/del(7) (n=3), or FUS::ERG (n=1). Seven patients were enrolled on DL1 (one NE, replaced); eight patients were enrolled on DL2 (two NE, replaced). In the DL1 cohort, one DLT was reported of grade 3 anorexia requiring nasogastric feeds; however, this was cofounded by a prior history of anorexia, mucositis, and poor dentition requiring extractions and restorations. At DL2, one patient experienced a hematologic DLT with failure to recover absolute neutrophil count above 500/uL and platelet count above 25,000/uL by day 43 from start of FLA(G). There were no DLTs in the other five evaluable patients in DL2 and no serious adverse events (AEs) reported. The most common Grade 3 or 4 AE was febrile neutropenia (16.7%). Of the evaluable patients, five of twelve (41.7%) achieved complete response (CR) or complete response with incomplete count recovery (CRi). One patient was an ER on Day 15 at DL2 and did not receive FLA(G); thus, this patient was not evaluable for DLT assessment. Six patients proceeded to hematopoietic cell transplant after protocol therapy, five of whom are alive to date. Conclusion: Venetoclax and selinexor with FLA(G) chemotherapy is a tolerable combination in pediatric and AYA patients with R/R AML. Early activity of this combination regimen was observed in some patients, including those with primary refractory or early first-relapsed AML. Enrollment of the dose expansion phase at DL2 is underway in two cohorts: venetoclax-naïve and venetoclax-exposed.

Phase I/II Study of Quizartinib, Venetoclax, and Decitabine Triple Combination in FLT3-ITD Mutated AML

Background: Patients (pts) newly diagnosed with FLT3-ITD mutated (m) acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy (IC) experience poor outcomes (Konopleva et al. 2022, Clin. Can. Res.). These patients have a median overall survival (OS) of 9.9 months when treated with the standard of care regimen (azacitidine and venetoclax). Aims: We evaluated the safety and efficacy of the triple combination of Quizartinib (Quiz), Venetoclax (VEN), and decitabine (DAC) in pts with relapsed/refractory (R/R) or newly diagnosed FLT3-ITDm AML. Methods: The study included a frontline cohort of pts ineligible for IC and an R/R cohort of pts who had received ≤ 5 prior treatments for AML (up to salvage 5). On Day 14, all pts underwent bone marrow (BM) evaluation, and VEN (400 mg/day or equivalent with azole) was discontinued on Day 14 for pts with BM blasts ≤ 5% (or marrow aplasia/hypocellularity). Pts with Day 14 BM blast &amp;gt;5% continued VEN for 21 days during cycle 1, followed by administration from days 1 to 14 in subsequent cycles, with further dose reductions based on count recovery. All pts received 10 days of DAC (20 mg/m2) for induction, followed by 5-day DAC in subsequent cycles. Quiz (30 or 40 mg/day) was continuously administered daily. Results: A total of 50 pts were enrolled, including 40 R/R and 10 newly FLT3-ITD mutated AML pts (Table 1). Among the 40 R/R AML pts (median 3 [range 1-5] prior AML therapies), 85% had received ≥1 prior FLT3 inhibitors (FLT3i's), with 78% having prior exposure to gilteritinib, and 40% having undergone prior allogeneic stem cell transplantation (ASCT). The rates of CRc, CR+CRi, measurable residual disease (MRD) negativity by multicolor flow cytometry (MFC, sensitivity 10 -4), and FLT3-PCR (sensitivity 10 -2 - 10 -3) negativity among the 40 R/R pts were 68%, 33%, 29% (7/24), and 36% (8/22), respectively (Table 2). The median number of cycles required to achieve a response was 1 (range 1-2). The 60-day mortality rate was 0%. With a median follow-up of 33 months, the median OS was 7.1 months, and the 1-year OS rate was 22% in this predominantly gilteritinib-exposed R/R cohort. Among the 31/40 prior gilteritinib exposed pts the CRc, CR+CRi, median OS and 1-year survival were 65%, 23%, 6.9 month, and 21%. Among the 9/10 prior gilteritinib naïve pts the CRc, CR+CRi, median OS and 1-year survival were 77%, 66%, 10.3 months and 25%. Among the newly diagnosed AML, all achieved CRc (7 CR, 3 CRi), with 9/10 (90%) and 7/9 (78%) evaluable responders being FLT3-PCR and MFC negative, respectively. All 10 pts achieved BM &amp;lt;5% or aplasia/hypocellularity on C1D14. With a median follow-up of 15 months, the median OS was not reached. No pts experienced dose-limiting toxicity (DLT) with Quiz 30 mg/day; however, with Quiz 40 mg/day, the first 2 pts treated developed hematologic DLT (grade 4 neutropenia with a &amp;lt;5% cellular bone marrow with no residual AML lasting ≥42 days). Consequently, Quiz 30 mg/day was declared the RP2D for this combination. In the R/R cohort, grade ≥3 non-hematologic toxicities regardless of attribution, occurring in &amp;gt;10% of pts, included pneumonia (73%), neutropenic fever (53%), sepsis (18%), bacteremia (15%), other infections involving the skin (18%), and gastrointestinal tract (13%). The incidence of grade ≥3 non-hematologic toxicities was less frequent in the frontline cohort, with pneumonia (40%), neutropenic fever (50%), sepsis (10%), bacteremia (20%), and no grade 3 QTcF prolongations observed. The median recovery times for absolute neutrophil count (ANC &amp;gt; 500/μL) and platelet (&amp;gt;50 x 109/L) were 43 days [13-138] and 49 days [21-67] for the R/R cohort, and 40 days [28-56] and 40 days [22-46] for the frontline cohort, respectively. In the frontline cohort, at the last follow-up, 7 pts were in complete remission (CR), 2 ps died with relapsed AML, and 1 pt died in remission postASCT. Among the 40 pts in the R/R cohort, 9 were still alive (7 in CR, 2 with relapsed disease), while 31 pts died (5 deaths in CR, 26 due to relapsed/refractory leukemia). Conclusion: The combination of DAC + VEN + Quiz demonstrated activity in heavily pretreated and prior FLT3i-exposed (including 78% with prior gilteritinib exposure) R/R FLT3-ITDm pts, with a CRc rate of 68% and a median OS of 7.1 months. In the frontline setting, all pts achieved CRc with no early mortality, median count recovery of 40 days, and median OS not reached. The study continues to accrue, and updated results will be reported at the meeting.

Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1).

Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug re-induction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50mg/m2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1-3) and subsequently combined with re-induction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50mg/m2 /dose orally for 21days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Palbociclib in combination with re-induction chemotherapy was well tolerated with a RP2D of 50mg/m2 /day for 21days. Complete responses were observed among heavily pretreated patients.

A Multi-Center Phase Ib Trial of the Histone Deactylase Inhibitor (HDACi) Entinostat in Combination with Anti-PD1 Antibody Pembrolizumab in Patients with Refractory/Relapsed Myelodysplastic Syndromes (RR-MDS) or Oligoblastic Acute Myeloid Leukemia (RR-AML) after Hypomethylating Agent (HMA) Failure

Introduction: Pts with MDS and HMA failure have a poor prognosis and need novel therapies. Success with anti-PD1 therapy in myeloid malignancies has been limited and resistance mechanisms are poorly understood. Preclinical data suggest that myeloid-derived suppressor cells (MDSCs) contribute to MDS progression (Chen et al. JCI 2013). and may mediate resistance to anti-PD1 therapy (Kim et al. PNAS 2014). As HDACi decrease MDSCs, synergistic anti-tumor efficacy with anti-PD-1 has been hypothesized leading to this phase Ib study (NCT02936752) of the HDACi entinostat and anti-PD1 antibody pembrolizumab in pts with MDS or oligoblastic AML and HMA failure. Methods: We conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program (NCI-CTEP)-sponsored, multicenter, dose escalation and expansion phase Ib trial. Adult (≥18 years) pts with MDS or oligoblastic AML (bone marrow [BM] blasts 20-30%) and HMA failure were enrolled. Pts had to have adequate end organ function and ECOG performance status ≤2. The dose-escalation part used 2 dose levels (DL1: entinostat 8mg PO on days 1 and 8 of each 21-day cycle; DL2: entinostat 8mg PO on days 1, 8, and 15 of each 21-day cycle) with pembrolizumab 200mg IV on day 1 of each 21-day cycle starting with cycle 2. In cycle 1, pts received only entinostat to determine its impact on MDSCs separately from pembrolizumab. Toxicities were tabulated and graded according to CTCAE-5. Dose-limiting toxicities (DLT) were defined as any of the following if deemed possibly related to trial therapy: Grade (G) 3/4 non-hematologic toxicity, any ≥G3 immune related adverse events (IrAEs) or any IrAE resulting in pembrolizumab interruption or discontinuation during the first 2 cycles of combined therapy. Hematologic AEs were considered a DLT only if they were unrelated to MDS and lasted for >42 days. The primary endpoint was safety and determination of the maximum tolerated dose. The secondary endpoint was the overall response rate defined as a composite of complete remission, partial remission, and hematologic improvement (HI) per the 2006 IWG response criteria in MDS and change in MDSCs and PD1/PDL-1 in BM. Results: Between 06/26/2017 and 02/03/2021, we enrolled 28 pts (25 MDS and 3 AML). Median age was 74 years (range [R], 57-86), all pts had received prior HMA with 5 pts (18%) having had ≥3 prior lines of therapy. Median IPSS-R at screening for MDS pts was 5.5 (R: 2-10). Baseline demographic and clinical characteristics are shown in Table 1. During dose escalation, 7 pts were enrolled in DL1 (1 pt not evaluable due to early disease progression during DLT period), and 6 pts were treated on DL2. There was 1 DLT on DL1 (G5 pneumonia/bronchoalveolar hemorrhage (BAH), while 2 pts experienced DLTs at DL2 (G3 pharyngeal mucositis and G3 anorexia). There were no hematologic DLTs during dose escalation. Thus, DL1 was expanded, and another 15 pts were enrolled at DL1. Across the entire study, pts received a median of 3 cycles of therapy (R: 1-12 cycles). The most frequent cause of treatment discontinuation was disease progression in 9 pts. Four pts died during the study, 2 due to therapy-related complications (1 from pneumonia/BAH, 1 from multi-organ failure which occurred after the DLT period in DL2). A summary of the AEs is presented in Table 2. Hematologic AEs were common. The most common non-hematologic ≥G3 AEs independent of treatment attribution were infection (32.1%), hypoxia/respiratory failure (10.7%) and dyspnea (10.7%). Potential IrAEs of any grade were reported in 5 pts including G3 pneumonitis in 2 pts. Serious AEs were reported in 14 pts; 8 of which were potentially attributed to treatment. Among the 19 pts with the first BM efficacy assessment after 3 months, no pt achieved a protocol-defined response. However, 2 pts had mCR (BM blasts decreased from a baseline of 7% and 10% to 2% and 4%, respectively) without HI. Twelve pts had stable disease, while 5 had progressive disease. With a median follow-up of 5.9 months (R: 0.5 - 59.1 months), median OS was 6.9 months (95% CI: 4.8 - 13.6 months). Correlative studies are being conducted. Conclusion: In this multi-center phase 1b investigator-initiated trial in MDS and oligoblastic AML pts after HMA failure, entinostat + pembrolizumab at DL1 was reasonably tolerated but had limited therapeutic efficacy. Ongoing correlative work will explore the disconnect between the preclinical and clinical data regarding potential synergy of entinostat + pembrolizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

Introduction: The safety and clinical activity of low-dose hypomethylating agents (HMAs; parenteral decitabine or azacitdine) for patients with LR-MDS has been reported (Jabbour et al, 2017). Oral decitabine/cedazuridine (ASTX727; fixed-dose combination of 35 mg decitabine/100 mg cedazuridine) is an oral DNMTi that provides equivalent exposure to intravenous decitabine at a standard dosing (SD) regimen (20 mg/m2 days 1-5 every 28 days; Garcia-Manero et al, 2020). An effective oral HMA therapy for patients with LR-MDS that reduces the number of transfusions while avoiding the toxicity associated with both myelosuppression and parenteral administration could ease the burden of HMA administration on patients and caregivers with potential improvement of quality of life. The Phase 1 part of this study explores the optimal dosing schedule of LD oral decitabine/cedazuridine in patients with LR-MDS. Methods: A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted at US and EU medical centers in subjects with LR-MDS (IPSS low risk and Int-1). Dose selection for the ASTX727-03 Phase 1 study was divided into two phases (Stage A and Stage B). Phase 1 Stage A was designed to approximate the total dose of intravenous (IV) DEC (20 mg/m2 for 5 days) over a longer dosing period and randomized subjects to 3 Cohort regimens of 5 (Cohort A1), 10 (Cohort A2), or 15 mg (Cohort A3) DEC /100 mg CED daily for 10 days in 28-day cycles. In Phase 1 Stage B, subjects were treated with the following 3 LD oral decitabine/cedazuridine regimens of shorter duration; Cohort B1: 10 mg DEC / 100 mg CED daily for 5 days, Cohort B2: 10 mg DEC / 100 mg CED daily for 7 days, Cohort B3: 20 mg DEC / 100 mg CED daily for 5 days. Primary endpoints include determination of dose-limiting toxicity (DLT), frequency and severity of treatment-emergent adverse events (TEAEs), and the recommended Phase 2 dose (RP2D). Secondary endpoints include: pharmacodynamic (PD) activity, pharmacokinetics (PK), and clinical activity based on International Working Group (IWG) 2006 MDS response criteria and transfusion independence, Leukemia Free survival (LFS), and overall survival (OS). Results: At the data cut-off date of June 17, 2022, 48 LR-MDS subjects were enrolled, and 47 received study treatment. Characteristics were: median age: 76 years (range 51 - 88), male: 31 (65%), and IPSS LR: 15 (31%) and Int-1: 33 (69%), respectively. The median duration of exposure is 9 cycles (range 1-34). In Stage A, cohort A2 (10 mg, 10-day) was closed due to hematologic DLT (see Table 1) in all four treated subjects, hence cohort A3 (15 mg, 10-day) was closed prior to any subjects being randomized to that regimen. The final number of subjects treated in cohorts A1 (5 mg, 10-day), A2, and A3 were 10, 4, and 0, respectively. In Stage B, 33 subjects were randomly assigned to cohorts B1 (10 mg, 5-day), B2 (10 mg, 7-day), or B3 (20 mg, 5-day), with 11 subjects each treated with the respective dosing schedules. DLT was observed in 3 (30%), 4 (100%), 3 (27%), 7 (70%), and 7 (64%) subjects in Cohorts A1, A2, B1, B2, and B3, respectively. The DLT incidences were proportional to the dose intensity (total DEC dose per cycle) and number of days of study drug administration. All DLTs were related to neutropenia and in general regimens with higher total doses of DEC per cycle (Cohorts A2 and B3) had deeper neutrophil nadirs while regimens with longer dosing periods (7-10 days; Cohorts A1, A2, and B2) required longer to recover neutrophil counts to baseline and dose reductions and dose delays were observed more frequently than in Cohort B1. Adverse events were similar to those reported for standard dose oral decitabine/cedazuridine, with the most common grade ≥ 3 TEAEs being neutropenia (36%), anemia (28%), and febrile neutropenia (19%). Clinical activity by dosing schedule is shown in Table 1, and bioavailability was confirmed by PK analysis. Of the 47 treated subjects, 22 subjects (47%) had reached the event of death as of the data cutoff date and median OS time was 929 days (95% CI: 526, NE). Median LFS was 690 days (95% CI: 428, 934). Conclusions: Based on the results of the Phase 1 study, the dosing schedule of 10 mg DEC / 100 mg CED daily for 5 days, that balanced clinical efficacy with an acceptable and manageable safety profile was selected as the RP2D. This regimen will be compared to 35 mg DEC / 100 mg CED for 3 days in a 28-day cycle in the ongoing Phase 2 study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Novel Combination Therapy of Venetoclax and Ruxolitinib in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia

Novel Combination Therapy of Venetoclax and Ruxolitinib in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia

FLT3-Mutated Acute Myeloid Leukemia Using a Novel Regimen of Gemtuzumab Ozogamicin and Midostaurin in Combination with Standard Cytarabine and Daunorubicin Induction Therapy

FLT3-Mutated Acute Myeloid Leukemia Using a Novel Regimen of Gemtuzumab Ozogamicin and Midostaurin in Combination with Standard Cytarabine and Daunorubicin Induction Therapy

Quizartinib (Quiz) with Decitabine (DAC) and Venetoclax (VEN) Is Highly Active in Patients (pts) with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) - RAS/MAPK Mutations Continue to Drive Primary and Secondary Resistance

Quizartinib (Quiz) with Decitabine (DAC) and Venetoclax (VEN) Is Highly Active in Patients (pts) with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) - RAS/MAPK Mutations Continue to Drive Primary and Secondary Resistance

Abstract 1145: AGX323 - A SAM-competitive, orally available inhibitor of protein arginine methyltransferase 5 (PRMT5) with potent cellular antiproliferative and in vivo antitumor activity against selected solid cancer types

Abstract Background: Protein arginine methyltransferase 5 (PRMT5) is an attractive therapeutic target because of its involvement in key oncogenic mechanisms including epigenetics, DNA response and RNA processing. Early development of PRMT5 inhibitors has focused on hematological malignancies although more recently several compounds have entered the clinic for both liquid and solid malignancies. Early Phase I clinical data indicate dose-limiting hematological toxicity, particularly anemia and thrombocytopenia. We focused our effort in discovering compounds with potent inhibitory activity against cells from solid cancer types known to overexpress PRMT5 and which correlated with poor prognosis (NSCLC, breast, bladder and pancreatic cancers). Methods: Enzyme inhibition was conducted using a PRMT5:MEP50 flash plate assay, with S-adenosylmethionine (SAM) as the methyl donor and histone H4 as substrate. Inhibition of cell proliferation was assessed in various cancer lines using a 7-day cellTitre-Glo (CTG) assay. Binding mode of the inhibitors to PRMT5 was investigated using surface plasmon resonance (SPR). In vivo antitumor activity was evaluated in various human cancer models grown in immunocompromised mice. Results: Structure activity relationship of a series of over 50 close analogs demonstrated that in vitro anticancer activities correlate poorly with enzyme inhibition potency. To understand this discrepancy we used SPR to study the PRMT5 binding mode of cell active and inactive compounds in the presence of various endogenous substrates (SAM, SAH or MTA). We obtained binding affinity (KD), association constant (Ka) and dissociation constant (Kd) of exemplars of active and inactive inhibitors and correlated their relationship to cell activity. The lead compound AGX323 has a KD of 1.8 x 10-10 M to SAM-bound PRMT5 and exhibited potent antiproliferative activity against a panel of over 20 human solid epithelial cancer cell lines from lung, breast, bladder and pancreas, with nM potency. For example, in the H1048 human lung cancer model it has an enzyme inhibition IC50 of 0.8 nM, a cell proliferation IC50 of 1.7 nM and when given to tumor bearing mice it demonstrated robust antitumor activity at well-tolerated dose levels. In nonclinical ADME studies, AGX323 demonstrated favorable drug-like properties: including acceptable oral bioavailability (in mouse, dog and monkey) and systemic exposure following oral administration, excellent metabolic stability, lack of significant drug-drug interaction liabilities (transporters, CYP inhibition, CYP induction). Conclusion: AGX323 demonstrated potentially best-in-class activity in PRMT5 dependent human solid cancer models and exhibited excellent drug-like properties. IND enabling studies are currently planned. Citation Format: Francis Y. F. Lee, Wen-Lian Wu, Zhiqiang Yang, John Tan. AGX323 - A SAM-competitive, orally available inhibitor of protein arginine methyltransferase 5 (PRMT5) with potent cellular antiproliferative and in vivo antitumor activity against selected solid cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1145.

Quizartinib with decitabine and venetoclax (triplet) is highly active in patients with FLT3-ITD mutated acute myeloid leukemia (AML).

e19019 Background: The outcomes in patients (pts) with newly diagnosed FLT3 mutated AML who are ineligible for intensive induction chemotherapy are poor. Added to a low intensity chemotherapy backbone, FLT3 inhibitors, such as midostaurin, sorafenib, and quizartinib, result in median OS of 8-17 months in the frontline (Gallogly ASH 2017, Ohanian AJH 2018, Swaminathan ASH 2017), and 4-8 months in relapsed/refractory (R/R) settings (Yilmaz JHO 2020, Ravandi Blood 2013). Quizartinib, a potent second generation FLT3 inhibitor demonstrated synergy with venetoclax (VEN) (a BCL-2 inhibitor) in AML cell lines and PDX models (Mali Haematologica 2020). We designed this study to evaluate the safety and efficacy of quizartinib, venetoclax, and decitabine combination in pts with R/R or newly diagnosed FLT3 mutated AML. Methods: Frontline cohort included pts who are ineligible for intensive induction chemotherapy, and R/R cohort included pts who received 5 or less prior treatments. All patients had a performance status of ECOG ≤2, adequate organ functions, and QTcF &lt;450 msec prior to therapy. All pts underwent day 14 bone marrow, and venetoclax (400 mg/day) was put on hold in patients with bone marrow blasts ≤ 5% (or marrow aplasia). Those with day14 bone marrow blast &gt;5% continued venetoclax for 21 days during cycle 1. All pts induced with 10 days of decitabine (20 mg/m2). In subsequent cycles, decitabine administered for 5 days. Quizartinib (30 or 40 mg/day) was administered daily continuously. Results: 21 pts were enrolled and 17 pts evaluable at the time of this report (4 are still within cycle 1). Of 13 pts with R/R AML (median 3 [range 1-5] prior therapies, 85% with ≥1 prior FLT3 inhibitor), 9 (69%) achieved CRc (2 CR, 7 CRi) with 4/9 and 5/9 responders FLT3-PCR and multicolor flow cytometry (MFC) negative, respectively. Thirty and 60-day mortality rates were 0% and 8%. Of 4 patients with newly diagnosed AML (median age 72), all achieved CRc (2 CR, 2 CRi) with 4/4 and 2/3 responders FLT3-PCR and MFC negative, respectively. 60-day mortality was 0% in the frontline cohort. No pts developed a dose limiting toxicity (DLT) with 30 mg/day quizartinib, however with the 40mg/day quizartinib 2 pts developed hematologic DLT (grade ≥3 neutropenia with a &lt;5% cellular bone marrow lasting ≥42 days). Hence, quizartinib 30 mg/day dose was determined as recommended phase 2 dose for the triplet. Grade 3/5 non-hematologic toxicities in &gt;2 pts included lung infections (N=9) and neutropenic fever (N=6). No QTcF prolongations &gt;450 msec were noted. With a median follow-up of 7.2 months, the median OS was not reached in frontline cohort and was 7.1 months in R/R cohort. 2/4 and 5/9 responders underwent ASCT in frontline and R/R cohorts, respectively. All frontline pts were alive at the last follow-up; 3 were in CR and 1 relapsed disease. Of 9 responders in R/R cohort, 4 were alive (3 CR, 1 relapse) and 5 died (4 relapse, 1 CR). Conclusions: Decitabine + venetoclax + quizartinib is highly active in R/R FLT3-ITD mutated AML pts, with CRc rates of 69% and the median OS of 7.1 months. Accrual to the triplet continues and updated clinical and correlative data will be presented. Clinical trial information: NCT03661307.

Abstract IA-006: Enhancing the therapeutic ratio for glioblastoma by combining radiation therapy with PARP inhibitors

Abstract PARP inhibitors (PARPi) enhance radiation sensitivity in multiple cancer models, both in vitro and in vivo. Our observation that the radiosensitizing properties of PARPi are most pronounced in rapidly proliferating cells is reflected in early phase clinical trial data showing exacerbation of acute radiation toxicity in rapidly proliferating tissues such as oropharyngeal and esophageal mucosa. Lack of radiosensitization in late responding, slowly proliferating normal tissues indicates that PARPi may be more effectively combined with radiation therapy (RT) in patients with brain tumors. We are therefore evaluating the oral PARPi olaparib in combination with RT and/or temozolomide (TMZ) in the treatment of glioblastoma (GBM), the most prevalent and most aggressive primary brain tumor. Patients with GBM experience very poor outcomes in terms of median survival (c.1 year) and neurocognitive decline caused primarily by RT. Olaparib was initially evaluated in combination with daily low-dose TMZ in patients with recurrent GBM in the OPARATIC trial. Pharmacokinetic studies revealed that olaparib penetrates both core and margin regions of GBM, indicating that the BBB is significantly disrupted throughout these tumors. Olaparib could be safely combined with daily TMZ (75 mg/m2), but intermittent olaparib dosing (150 mg three days per week) was required to avoid dose-limiting hematological toxicity. Early phase testing of the olaparib-radiotherapy combination is now underway in three populations of patients with newly diagnosed GBM. Patients aged &amp;gt;65 with MGMT unmethylated GBM are being recruited to a randomized, placebo-controlled phase II study (PARADIGM) after a phase I dose escalation study showed that olaparib (200 mg twice daily) was extremely well tolerated when combined with brain irradiation (40 Gray in 15#). Good performance status patients aged &amp;lt;70 are being recruited to two parallel phase I dose escalation studies: patients with MGMT unmethylated tumors are receiving daily olaparib with RT (60 Gy in 30#) without TMZ, while patients with MGMT methylated tumors are receiving intermittent olaparib with standard chemoradiation (60 Gy). The impact of PARPi on RT induced neurotoxicity is being investigated in preclinical studies. In vitro data show that PARPi reduce proliferation of neural stem cells and protect them against RT induced apoptosis, while in vivo studies support the emerging concept that RT induced neuroinflammation is important in the pathogenesis of neurotoxicity. Importantly, preliminary PET and immunohistochemical studies have shown robust anti-neuroinflammatory effects of PARPi in this context. Ongoing experiments are defining the roles of microglia, astrocytes and neurogenesis in this phenomenon. These diverse data sets provide support for our hypothesis that combining PARPi with RT has potential to improve outcomes for GBM patients by enhancing tumor control while simultaneously suppressing neuroinflammation and alleviating RT related neurocognitive decline. Citation Format: Anthony J. Chalmers, Rodrigo Gutierrez-Quintana, David J. Walker, Karin Williams, Duncan Forster, Mark R. Jackson, Sarah Derby, Jon Stobo, Lorna Sweeting, Caroline Kelly, Stephen Durant, Kaye J. Williams. Enhancing the therapeutic ratio for glioblastoma by combining radiation therapy with PARP inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-006.

Phase I dose escalation study of 12b80 (hydroxybisphosphonate linked doxorubicin) in naturally occurring osteosarcoma.

Purpose: 12b80 combines doxorubicin bound to a bone targeting hydroxybisphosphonate vector using a pH-sensitive linker, designed to specifically trigger doxorubicin release in an acidic bone tumor microenvironment. This phase I study aimed to determine the safety and toxicity profiles of 12b80 in dogs with naturally occurring osteosarcoma, with the objective to translate findings from dogs to humans.Experimental Design: Ten client-owned dogs with osteosarcoma were enrolled in an accelerated dose-titration design followed by 3 + 3 design. Dogs received three cycles of 12b80 intravenous injection at 4 mg/kg (n = 1), 6 mg/kg (n = 2), 8 mg/kg (n = 3), and 10 mg/kg (n = 4). Endpoints included safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicity (DLT).Results: The MTD of 12b80 was 8 mg/kg (i.e., equivalent dose of doxorubicin of 110 mg/m2, range: 93–126). Most adverse events included grade ≤ 2 gastrointestinal disorders and hypersensitivity reactions. No hematological or cardiac DLT were observed at any dose tested.Conclusions: In dogs, 12b80 is overall well tolerated and expends the MTD of doxorubicin up to four times the standard dose of 30 mg/m2. These results demonstrate the potential therapeutic benefit of 12b80 in canine and human osteosarcoma.

Safety of Palbociclib in Combination with Chemotherapy in Pediatric and Young Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia and Lymphoma: A Children's Oncology Group Pilot Study

Background: Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (B-ALL, T-ALL, B-LLy and T-LLy), the outcome of patients with primary resistant or relapsed disease remains very poor, particularly for children with second or greater relapses and with T-cell disease. Deregulation of cell cycle machinery is essential for both the induction and progression of ALL (Sicinska et al. Cancer Cell 4:451-61, 2003). Additionally, targeting cell cycle regulators CDK4 and 6 efficiently suppresses ALL growth and disease progression in vivo (Sawei et al. Cancer Cell 22:452-65, 2012) and this effect is augmented by conventional chemotherapy. These data provided the rationale for investigating the CDK4/6 inhibitor palbociclib in relapsed/refractory ALL and LLy. Preliminary results from the ongoing Children's Oncology Group (COG) AINV18P1 trial are reported. Methods: Patients aged 1-30 years with first or greater isolated or combined marrow relapses of T-ALL or T-LLy and second or greater relapses of B-ALL or B-LLy are eligible for COG AINV18P1 (NCT03792256). Patients with refractory disease with at least 2 prior induction attempts or first relapse refractory to at least one prior re-induction attempt are also eligible. This is a 2-part study conducted at selected COG sites. In Part 1 of the study (dose determination), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy (Table 1). Study treatment consisted of a single cycle of therapy. A starting palbociclib dose of 50 mg/m2/dose was explored with one dose de-escalation (35 mg/m2/dose) using the rolling six design to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Part 2 (expansion cohort) is accruing 6 additional patients (pts) at the MTD for further assessment of the safety and feasibility of combination therapy. Dose-limiting toxicities (DLTs), defined as hematologic and non-hematologic toxicities exceeding baseline toxicities observed with re-induction chemotherapy alone, are assessed throughout the treatment cycle. The primary aims of the study are safety, determination of the MTD/RP2D and assessment of palbociclib pharmacokinetics (PK). Secondary aims are assessment of the biological and preliminary clinical activity of combination therapy in this patient population. Results: As of June 30, 2020, 8 pts have enrolled; 6 in Part 1 and 2 in Part 2. All 6 pts in Part 1 completed one full cycle (32 days) of protocol therapy. The median (range) age of pts is 10 (6-21) years and 62% are male (Table 2). Three pts had T-ALL, 4 B-ALL and 1 T-LLy. Pts received a median (range) of 2 (1-6) prior chemotherapy regimens and 2 pts underwent prior allogeneic stem cell transplant. All 6 pts in Part 1 experienced grade 3-4 toxicities, most commonly hematologic: anemia (3 pts), neutropenia (5 pts) and thrombocytopenia (4 pts). Three pts had grade 3 infections and one pt had grade 3 hyperbilirubinemia, which resolved. No hematologic or non-hematologic DLTs were observed at the 50 mg/m2/dose of palbociclib in Part 1 and accrual to the expansion phase of the trial at this dose continues. PK and pharmacodynamic studies assessing cell cycle inhibition are also ongoing. Conclusions: Palbociclib in combination with 4-drug re-induction chemotherapy is safe and well tolerated in children and young adults with relapsed/refractory ALL and LLy. Further assessment of the feasibility and activity of combination therapy is ongoing in the expansion phase of this trial. Disclosures Raetz: Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Teachey:La Roche: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sobi: Consultancy. Norris:Merck: Other: Travel funding. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. OffLabel Disclosure: This study includes off-label use of palbociclib in children and young adults with relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma.