Experienced Dose-limiting Toxicity Research Articles

First-in-Human Study of BAT4406F, an ADCC-Enhanced Fully Humanized Anti-CD20 Monoclonal Antibody in Patients With Neuromyelitis Optica Spectrum Disorders.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the central nervous system (CNS). This is the first-in-human dose-escalation Phase I clinical study of BAT4406F, an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced fully humanized anti-CD20 monoclonal antibody, in Chinese NMOSD patients. Using a "3 + 3" design and based on the planned algorithm of dose escalation, the enrolled NMOSD patients were sequentially assigned to one of the five dose-escalation cohorts of BAT4406F with a single intravenous dose, and were then followed for a 6-month observation period. The maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of BAT4406F were investigated, and the efficacy of BAT4406F in NMOSD was also preliminarily explored. Fifteen Chinese NMOSD patients were enrolled to receive BAT4406F of escalated doses ranging from 20 to 750 mg. No subjects experienced DLT at the studied doses. BAT4406F injection exhibited favorable safety, with most of the adverse events (AE) of CTCAE Grade 1 or 2 in severity, and no Grade ≥ 3 adverse drug reactions (ADR) or serious adverse reactions occurred in any subjects. With the dose increase of BAT4406F, the maximum plasma concentration (Cmax), area under concentration-time curve from 0 to the last measurable timepoint (AUC0-t) and area under concentration-time curve from 0 to infinity (AUC0-inf) showed an increasing trend, whereas the mean clearance (CLt), terminal elimination rate (λZ), and apparent volume of distribution (Vd) decreased. The mean elimination half-life (T1/2) was ranged from 9.0-16.4 days. PK profile of BAT4406F was generally nonlinear. BAT4406F led to a rapid and significant B-cell depletion in all dose groups. Single administration of 500 mg or 750 mg maintains the CD19+ B lymphocyte count below 10/μL within the whole 6-month observation period. Three subjects were antidrug antibody (ADA) positive and all of them were neutralizing antibody (NAb)-negative. On day 99/180 postdose, several groups had decreased expanded disability status scale (EDSS) scores compared to baseline. During the observation period, NMOSD relapse occurred in two patients (13.3%) and the other 13 (86.7%) subjects remained relapse free. BAT4406F was well tolerated at doses up to 750 mg and showed an expected pharmacodynamic effect of significant and long-term depletion of CD19+ B lymphocytes. It has also shown preliminary evidence of activity in NMOSD maintenance treatment, warranting further investigations. ClinicalTrials.gov identifier: NCT04146285.

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

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

A phase 1 trial of venetoclax in combination with liposomal vincristine in patients with relapsed or refractory B-cell or T-cell acute lymphoblastic leukemia: Results from the ECOG-ACRIN EA9152 protocol.

Relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B- and T-ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L-VCR and VEN for patients with r/r B-or T-cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644). In a 3+3 dose escalation design, r/r ALL subjects were given single-agent VEN doses reaching 400, 600, or 800mg for the three respective dose levels. Weekly L-VCR at 2.25mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination. Among the 18 patients in phase I, grade≥3 treatment-related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose-limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600mg). Twenty-two percent of evaluable patients (N=4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD). The combination of VEN and L-VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L-VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). TDM reduced the proportion of patients with subtherapeutic exposure levels by ~50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

A phase-I study of second-line S-IROX for unresectable pancreatic cancer after gemcitabine plus nab-paclitaxel failure.

Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 120mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 150mg/m2).

A Phase I/II Study of Valemetostat (DS-3201b), an EZH1/2 Inhibitor, in Combination with Irinotecan in Patients with Recurrent Small-Cell Lung Cancer.

Recurrent small-cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted. This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety, tolerability, and a recommended phase II dose (RP2D). The phase II primary objective was overall response rate (ORR), with secondary objectives of determining duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Correlative analyses included immunohistochemistry of pretreatment and on-treatment tumor biopsies and pharmacokinetics analysis. Twenty-two patients were enrolled (phase I, n = 12; phase II, n = 10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLT) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; three patients discontinued treatment for toxicity. Three of the first 10 patients in phase II experienced DLTs triggering a stopping rule. The ORR was 4/19 or 21% [95% confidence interval (CI), 6%-46%]. The median DoR, PFS, and OS were 4.6 months, 2.2 months (95% CI, 1.3-7.6 months), and 6.6 months (95% CI, 4.3 to not reached), respectively. SLFN11/EZH2 expression and SCLC subtyping markers did not correlate with response, but MHC-I expression did increase with treatment. Two responders demonstrated subtype switching on treatment. Combination valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat, combined with agents without overlapping toxicity, warrants further investigation in SCLC.

A phase 1 study of biweekly nab-paclitaxel/oxaliplatin/S-1/LV for advanced upper gastrointestinal cancers: TCOG T1216 study.

Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers. A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively. The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation. NCT03162510.

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

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

Abstract PO2-05-05: ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC)

Abstract Background: Currently, there are no approved systemic treatment options specifically for patients with ER+/HER2- BC who have brain metastasis. The prevalence of brain metastases from ER+/HER2- BC is approximately 14% of women (Aversa, 2014). Elacestrant is a next-generation oral SERD that was evaluated in a pivotal phase 3 trial, EMERALD, as monotherapy vs. standard of care (SOC) endocrine therapy. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC endocrine therapy in patients with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following progression on prior endocrine therapy (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. A clinical study in healthy postmenopausal women demonstrated the ability of elacestrant to cross the blood-brain barrier (Conlan, 2020). Abemaciclib, a CDK4/6i, has been shown to achieve therapeutic concentrations in brain metastases tissue (Tolaney, 2020). Given the lack of current systemic treatments, elacestrant is now being evaluated with abemaciclib in patients with ER+/HER2- BC and brain metastasis (NCT05386108). Methods: ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib in patients with brain metastasis from ER+, HER2- BC. Eligibility are patients with ER+/HER2− locally advanced or mBC and measurable brain metastasis. For phase 1b, the presence of brain metastases is allowed but not required for eligibility. For phase 2, patients must have ≥ 1 active and measurable brain metastasis per RECIST v1.1. Patients must have received prior therapy in the metastatic setting, including ≥ 1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The primary objectives of Phase 1b are to determine the recommended Phase 2 dose (RP2D). Phase 1b secondary objectives include safety, PK, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), PFS, and overall survival (OS). Phase 2 primary objective is ORR per RECIST version 1.1. Phase 2 secondary objectives include intracranial response rate (RR), DoR, CBR, PFS, OS, PK, and quality of life (QoL). The phase 1b portion evaluated dose-limiting toxicities (DLTs) of the combination during the first cycle (28 days) of treatment in up to three 6-patient cohorts, starting at elacestrant 300 mg daily plus abemaciclib 100 mg twice daily. Here we report initial safety results from the phase 1b portion. Results: As of June 2023, 15 patients have been enrolled in the phase 1b portion of the trial. At dose level 1, elacestrant 300 mg QD + abemaciclib 100 mg BID, no patient experienced DLTs, and the combination was feasible. Dose level 2, elacestrant 400 mg QD + abemaciclib 100 mg BID has been completed, and no patients experienced DLTs. In dose level 1, 4/7 patients remain on treatment at cycle 5. Additional safety and PK data for the cohorts will be provided. Conclusion: In the phase 1b portion of ELECTRA, dose level 1 and dose level 2 have been completed. No patients experienced DLTs in either dose level 1 or dose level 2, and the combination was considered feasible in the respective dose levels. Dose level 3 (elacestrant 400 mg QD + abemaciclib 150 mg BID) is proceeding. Recruitment is actively ongoing, enabling oral-oral combinations to determine a RP2D. Citation Format: Nuhad Ibrahim, Sung-Bae Kim, Nancy Lin, Ahmad Awada, Eva Ciruelos Gil, Giulia Tonini, Bartomeu Piza Vallespir, Kathy Puvana Theall, Erika Hamilton. ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-05.

Preliminary efficacy and safety of YSCH-01 in patients with advanced solid tumors: an investigator-initiated trial

ObjectiveTo evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors.MethodsIn this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid...

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

Purpose5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU.Patients and methodsNUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity.ResultsFifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival.ConclusionNUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies.Trial registrationClinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240.

Phase 1 Study of Bortezomib, Fludarabine, and Melphalan, With or Without Total Marrow Irradiation, as Allogeneic Hematopoietic Stem Cell Transplant Conditioning for High-risk or Relapsed/Refractory Multiple Myeloma.

We conducted a phase 1 study of a conditioning regimen with or without total marrow irradiation (TMI) before allogeneic hematopoietic stem cell transplantation for patients with high-risk or refractory multiple myeloma. Eighteen patients were enrolled on one of 2 strata. Patients with no prior radiation received TMI (900 cGy), fludarabine (FLU), and melphalan (MEL) conditioning, with bortezomib added in the second cohort (stratum I). Patients with prior radiation received FLU, MEL, and bortezomib, without TMI (stratum II). Eight patients were enrolled in the TMI arm (stratum I). One of 3 patients in cohort 1 experienced dose-limiting toxicity (DLT), which led to the expansion to 3 more patients with no DLT. Cohort 2 enrolled only 2 patients due to low accrual, with bortezomib, added at 0.5 mg/m 2 ; neither experienced DLT. Nine patients were enrolled in the non-TMI arm (stratum II). Three patients were enrolled in cohort 1 (bortezomib 0.5 mg/m 2 ) and none experienced DLT. Three were enrolled in cohort 2 (bortezomib 0.7 mg/m 2 ), and 1 experienced DLT; therefore, the cohort expanded to 3 more patients. One more patient experienced DLT. Median overall survival on strata I and II was 44.5 months (95% CI: 1.73-not reached) and 21.6 months (95% CI: 4.1-72.7), respectively. Median progression-free survival on strata I and II was 18.1 months (95% CI: 1.73-not reached) and 8.9 months (95% CI: 2.7-24.4), respectively. TMI 900 cGy, FLU, and MEL are considered feasible as conditioning for allogeneic stem cell transplantation and may warrant further investigation due to favorable response rates and survival.

Gemcitabine and nab-paclitaxel combined with afatinib in metastatic pancreatic cancer – Results of a phase 1b clinical trial

PurposeThe combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC. MethodsTreatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m2 / 125 mg/m2 (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy. ResultsTwelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3–5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months. ConclusionsIn this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m2 / 125 mg/m2) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.

Phase I dose-escalation study of nab-paclitaxel combined with cisplatin and capecitabin as induction chemotherapy followed by concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma

Background and purposeNab-paclitaxel is a promising albumin-bound paclitaxel with a therapeutic index superior to that of docetaxel, but the optimal dose of nab-paclitaxel combined with cisplatin and capecitabine as induction chemotherapy followed by concurrent chemoradiotherapy for patients with locally advanced nasopharyngeal carcinoma remains unknown. Materials and methodsThis was an open-label, single-arm study investigating the safety and efficacy of nab-paclitaxel + cisplatin + capecitabin as IC for three cycles, followed by cisplatin CCRT, conducted by using the standard “3 + 3” design in LA-NPC. If more than one-third of the patients in a cohort experienced dose-limiting toxicity (DLT), the dose used in the previous cohort was designated the maximum tolerated dose (MTD). The recommended phase 2 dose (RP2D) was defined as one level below the MTD. ResultsFrom 29 May 2021 to 17 March 2022, 19 patients with LA-NPC were enrolled, one patient withdrew informed consent. Two DLTs occurred in cohort 4 (grade 4 febrile neutropenia and grade 3 peripheral neuropathy), and an MTD was established as 225 mg/m2. The most frequent grade 3 or 4 adverse events were neutropenia (16.7 %), hypertriglyceridemia (16.7 %), leukopenia (5.6 %) and peripheral neuropathy (5.6 %) during IC. ConclusionThe RP2D is nab-paclitaxel 200 mg/m2 on day 1, combined with cisplatin 75 mg/mg2 on day 1 and capecitabin1000 mg/m2 on days 1–14, twice a day, every 3 weeks, for three cycles as an IC regimen prior to CCRT.Trial registration:ClinicalTrials.gov Identifier: NCT04850235.

Pharmacokinetics (PK) of Deferasirox in Transfusion Dependent Thalassemia

Iron overload is a major cause of organ dysfunction and death in transfusion-dependent thalassemia (TDT) and advances in iron chelation are urgently needed. The iron chelator, deferasirox, is widely used in TDT, however, many patients accumulate iron despite taking maximum recommended doses and many experience dose-limiting toxicity, including renal and liver failure. There is high inter-individual variability in the plasma concentrations of patients taking comparable deferasirox doses and low exposure correlates with inadequate chelation response. The cause of variable drug levels remains unknown, in part because prior deferasirox PK studies primarily include limited sample sizes and/or homogenous patients. There is an urgent unmet need to determine (1) what patient characteristics contribute to the observed variability in deferasirox-plasma concentrations, and (2) how dosing strategies can be tailored to achieve optimal therapeutic plasma-drug concentrations in all patients. We initiated a 2 year, single center observational pharmacokinetic (PK) pilot study to describe the PK of deferasirox in a diverse group of TDT patients from 2 years old through adulthood with a goal accrual of 50 patients. Our aim is to develop a population PK (popPK) model of deferasirox that will be evaluated in a future prospective study to individualize dosing and optimize exposure. The eligibility criteria are broad to capture a diverse population. Patients are eligible if they: 1) have a diagnosis of TDT, 2) are taking deferasirox, and 3) are able to provide informed consent (or have a guardian provide informed consent). For quantification of plasma deferasirox concentrations, 0.5 ml of whole blood are collected prior to transfusions at 4 regularly scheduled transfusion visits. Samples are then analyzed by a validated high performance liquid chromatography assay. Baseline labs, liver iron concentration and information on concomitant chelators are collected at the start of the study and labs, fed/fasted state, time and dose of last deferasirox, deferasirox regimen, and concomitant chelators are collected at each study visit. The planned analysis is to use nonlinear mixed effect modeling to calculate drug exposure and develop the popPK model. We have enrolled 39 patients with TDT, including 27 patients with beta thalassemia major, 10 patients with hemoglobin E beta thalassemia, 12 patients with hemoglobin H constant spring and one patient with beta thalassemia intermedia. Median age is 28 years old, with a range from 6 - 63 years old. Pre-study iron status also varied considerably, with median liver iron concentration 4.5 mg/g (range 1.5 -30 mg/g) and median ferritin 1500 ug/L (range 460 - 5600 ug/L). Thirty one patients have completed the study and 141 samples have been collected. Initial analysis of the first 15 patients who completed the study show a wide range of steady state plasma-deferasirox concentrations, consistent with prior reports. The means for the 4 samples collected per patient were calculated and found to have a median of 36.3 ug/ml with a range of 13.4 - 56.0 ug/ml. For the individual sample collections, the range of plasma deferasirox concentrations was even greater (0.18 - 99.9 ug/ml). These results need to be analyzed further to account for the dosing regimen, iron burden and other individual patient characteristics. In this study, we also collected genomic DNA from the buffy coat to evaluate the impact of single nucleotide polymorphisms in enzymes involved in drug metabolism and distribution. Once all data is collected, we will evaluate whether patient age, weight, laboratory values, fed/fasted state, concomitant chelators or pharmacogenomics impact deferasirox serum concentrations and can inform individualized deferasirox dosing. This study is unique, unlike prior deferasirox PK studies which collected intensive PK, we are using sparse sampling to collect real world data on deferasirox at steady state in TDT patients. Our hope is that this study will enable safer more effective dosing of deferasirox in patients with TDT.

The Final Results of a Phase I Study Using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium sized B cell lymphoma. No standardized treatment exists for this disease. Cladribine is a hypomethylating agent that indirectly down-regulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Bortezomib (Velcade) is an FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this study, we evaluated the safety and efficacy of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL. Patients and Methods: This is a single arm open label phase I trial. This study employed a standard 3+3 dose escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. Briefly, the treatment scheme was consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m 2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3 to 5 mg/m 2 (3 mg/m 2 for level 1, 4 mg/m 2 for level 2, and 5 mg/m 2 for level 3) infusion was given on days 1 to 5 for 6 cycles. For patient older than 70 years old, Cladribine was only given on days 1 to 3 of each cycle. Velcade 1.6 mg/m 2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1 to 3, Days 5 and 19 for Cycles 4 to 6, then once per month as maintenance therapy. The primary endpoint of this study was the dose limiting toxicity (DLT), safety, and efficacy of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression free survival (PFS) and overall survival (OS) (Figure 1). The analysis was done by intent to treat. Differentially methylated region (DMR) analysis and cytokine assay were performed to explore biomarkers differentiating good-responders from poor-responders. Results: This study recruited 13 patients, with a median age of 64 years old (range from 55 to 83) and including 11 males and 2 females. Ten patients were never previously treated, other 3 either relapsed or failed from previous treatments. Most patients tolerated this regimen well. No patient experienced DLT at either level 1 or 2, one possible DLT (infectious colitis) was observed during 2nd cycle at level 3. Two relapsed patients experienced disease progression after received two cycles of treatment and died in 5 and 7 months. Another patient died in 15 months after receiving treatment. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 77% (10/13). In newly diagnosed patient cohort, CR rate was 100% (10/10), OS rates were 90% (9/10), and PFS was 80% (8/10), of which 3 patients have been followed for more than 4 years, 3 other patients for more than 3 years, and 3 others for over 2 years (Fig.1). In relapsed/refractory patient cohort, 1 achieved CR for 7 months but then relapsed, 2 had no response. There were 2 blastoid patients, 1 of these 2 patients was newly diagnosed and achieved CR. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Cytokine assay showed decreased CXCL12 level in the good responders. Though global methylation pattern showed no difference, DMRs were identified in the good responders and the poor responders. DMRs-related genes involved in CXCL2 pathways were further extracted and enriched biological process analysis revealed the pathway profile difference between good responders and poor responders. Good responders exhibited alternation of apoptotic and Wnt signaling pathways (Fig.2). Conclusions: The VCR combination is a well-tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m 2 is a tolerable dose with manageable toxicity. Individual patient methylation profile may affect response to VCR therapy.

Phase 1/2a Trial of Bomedemstat with or without All- Trans Retinoic Acid (ATRA) in Advanced Myeloid Malignancies

Background: Acute myeloid leukemia (AML) is a devastating disease difficult to treat. Although &amp;gt; 60% of patients (pts) with AML treated with standard therapy achieve complete remission, at least 70% relapse. Overexpression of lysine-specific demethylase 1 (LSD1) mRNA and excess LSD1 protein have been observed in several cancer types, including progenitor populations of leukemic cells in AML. In preclinical studies, LSD1 inhibition impaired tumor growth and induced apoptosis of leukemic cells (Harris et al., 2012). In combination with ATRA, LSD1 inhibition enhanced survival in mouse models of AML (Shenck et al., 2014). In this first-in-human trial, we examine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of bomedemstat with or without ATRA in pts with high-risk AML and myelodysplastic syndrome (MDS). Methods: In this multicenter, open-label phase 1/2a trial, eligible pts were aged ≥18 years old, with high-risk AML or MDS, ECOG PS ≤2 (AML), and International Prognostic Score (IPSS) of at least intermediate-2 or Revised International Prognostic Score (IPSS-R) of at least intermediate (MDS). Pts could not have received immunotherapy within &amp;lt;8 weeks, chemotherapy within &amp;lt;3 weeks (except hydroxyurea), and radiation to &amp;gt;30% of marrow within &amp;lt;2 weeks of treatment. In the dose-finding phase, pts received bomedemstat at a starting dose of 0.75, 1.5, 3.0, or 6.0 mg/kg once-daily in 14-day cycles (7 days on, 7 days off), either alone or in combination with 45 mg/m 2ATRA for up to 4 cycles. Treatment was allowed to continue upon evidence of clinical benefit. In the duration-finding phase, pts received 6.0 mg/kg bomedemstat with ATRA in 21-day (14 days on, 7 days off) or 28-day (21 days on, 7 days off) cycles. Treatment continued until progression, unacceptable toxicity, or withdrawal. Primary endpoint was safety and tolerability. Secondary endpoints included PK parameters and PD effect on hematopoiesis. Clinical responses were documented per revised/modified Cheson criteria. Data cut-off date was December 13, 2018. Results: A total of 45 pts enrolled with a median age 73 years (range, 42 to 88); 19 (42%) were female. A total of 39 pts had AML with 27 (69%) having an ECOG PS score ≤1. Six pts had MDS with 2 (33%) pts having an IPSS of Very High Risk and IPSS-R of High Risk. A total of 33 pts were enrolled in the dose-finding phase (0.75 mg/kg/d bomedemstat [n=3], 1.5 mg/kg/d [n=6], 3.0 mg/kg/d [n=4], 6.0 mg/kg [n=6], 3.0 mg/kg + ATRA [n=5], 6.0 mg/kg + ATRA [n=9]). Twelve pts enrolled in the duration finding phase, 4 received bomedemstat plus ATRA for 14/28 days, and 8 received bomedemstat plus ATRA for 21/28 days. A total of 21 (47%) pts discontinued, 8 (18%) due to death, 5 (11%) due to withdrawal and 4 (9%) due to physician decision. Any grade adverse events (AE) related to bomedemstat occurred in 42 (93%) pts. The most common were diarrhea (42%), nausea (42%), and thrombocytopenia (38%). Grade ≥3 bomedemstat-related AEs occurred in 30 (66.7%) pts. One pt receiving 6.0 m/kg plus ATRA had a grade 5 AE related to bomedemstat due to respiratory failure. No patient experienced dose-limiting toxicity and no maximum tolerated dose was determined. The table summarizes PK parameters in whole plasma for the dose-finding phase. Based on plasma exposures, the Data Safety Monitoring Committee designated 6.0 mg/kg bomedemstat as the PD dose. Mean percent change (standard deviation) in blast counts was 368% (400) for pts receiving 0.75 mg/kg bomedemstat, 2478% (3279) for 1.5 mg/kg, 10% (25) for 3 mg/kg, 2841% (6047) for 6 mg/kg/d. For pts with AML, overall median EFS was 0.97 months (mo) (95% CI, 0.93-1.46), and median OS was 18.8 mo (95% CI, 3.86 to NR). The 6-mo rate for EFS and OS were 9% (95% CI, 0-46%) and 64% (95% CI, 25%-86%), respectively. The overall response rate was 28.2% (95% CI, 15.0-44.9, [1 PR, 10 SD]). For pts with MDS, median EFS was 0.93 mo (95% CI, 0.57 to NR) and median OS was NR (95% CI, 0.57 to NR). One pt with MDS had SD as best response (95% CI, 0.4-64.1). Conclusions: Bomedemstat up to 6.0 mg/kg alone or in combination with ATRA was well-tolerated in pts with high-risk AML or MDS. Change in blast count seen in treated pts could be due to differentiation to monocytes induced by bomedemstat rather than blast count reduction per se. Objective responses were seen in a subset of pts with AML (28%). OS was numerically higher to historical data with standard of care. Bomedemstat is currently under investigation in myeloproliferative neoplasms.

RTID-07. A RANDOMIZED WINDOW OF OPPORTUNITY TRIAL WITH DOSE ESCALATION TO EVALUATE FLUOXETINE AND TEMOZOLOMIDE IN GLIOMA

Abstract The blood brain barrier limits the efficacy of many drugs in brain tumors. Fluoxetine (Prozac) is FDA-approved and brain penetrant. Preclinical studies show synergy between fluoxetine and temozolomide (TMZ), resulting in lysosomal stress and enhanced DNA damage in human-derived glioma in vitro and in vivo. We present our randomized surgical window of opportunity trial (NCT05634707) in patients with recurrent IDH wild type glioma. The primary objective is to evaluate if fluoxetine induces tumoral lysosomal stress while exploratory objectives will determine if combination therapy enhances tumor DNA damage. We will randomize 30 patients, ≥ 24yo, with recurrent glioma and who are eligible for re-treatment with TMZ (MGMT methylated, progression &amp;gt;6 months post TMZ). Following informed consent, patients will be randomized 1:2 to control or experimental arms. Control patients will receive 50 mg/m2 TMZ for 7 days pre-resection. The experimental arm will receive 20 mg/day fluoxetine for 5 days before escalating to 40 mg/day. If &amp;lt; 3/10 participants receiving 40mg/day experience dose-limiting toxicity (DLT), subsequent experimental arm patients will escalate to 60 mg/day. All experimental arm participants will receive 50 mg/m2 TMZ for 7 days after starting fluoxetine, starting 21 days pre-resection. The regimen of 50 mg/m2 TMZ for 7 days is based on a similar pre-surgical trial combining TMZ with experimental therapy (NCT05188508). This reduced dose was chosen to limit potential synergistic toxicities like thrombocytopenia or neutropenia. Following resection, patients will continue TMZ, initially at reduced dose for the first post-op cycle, before reverting to standard doses of 150-200mg/m2 (up to 12 cycles or progression). All patients (control and experimental) will be offered fluoxetine post-operatively. The primary study outcome will be quantification of tumoral lysosomal stress via Lysosomal-associated membrane protein 1 (LAMP1) expression while DNA damage will be assessed via γH2A histone family member X (γH2AX) using immunohistochemistry.

CD33 CAR T-Cells (CD33CART) for Children and Young Adults with Relapsed/Refractory AML: Dose-Escalation Results from a Phase I/II Multicenter Trial

Introduction: Current therapies for patients with acute myeloid leukemia (AML) push the limits of chemotherapy intensity but cure only 30% of adults and 70% of children. Recently developed antibody-based therapies and molecularly-targeted agents only modestly improve outcomes for select patient subsets. Thus, new approaches are needed. Given the success of chimeric antigen receptor (CAR) T-cell therapies for acute lymphoblastic leukemia (ALL), we developed and optimized a novel CD33 CAR T-cell (CD33CART) construct for clinical testing in a multicenter Phase I/II clinical trial in children, adolescents, and young adults (AYA) with relapsed/refractory (r/r) AML. ( Qin H, et al. JITC 2021) We report interim results following completion of the dose-escalation phase. Methods: This multicenter phase I/II clinical trial (NCT03971799) was conducted as a 3+3 dose escalation study through the Pediatric Transplantation and Cell Therapy Consortium with National Marrow Donor Program sponsorship and managed by CIBMTR CRO. Autologous CD33CART product were centrally manufactured on a ClinicMACS Prodigy® by the Biopharmaceutical Development Program at the Frederick National Laboratory for Cancer Research (NCI). Eligibility criteria were r/r AML in subjects &amp;lt; 35 years old with adequate organ/performance status and an identified allogeneic stem cell transplant (SCT) donor. Bone marrow assessment was used for standard morphologic evaluation and central flow cytometric minimal residual disease (MRD) quantification. All subjects received pre-CD33CART lymphodepleting chemotherapy (LD) with fludarabine (75-120 mg/m 2) and cyclophosphamide (900-1000 mg/m 2). CD33CART doses levels (DLs) were: DL1: 3 x 10 5 CD33 CAR+ T-cells/kg; DL2: 1 x 10 6/kg; DL3: 3 x 10 6/kg and DL4: 1 x 10 7/kg. Adverse event grading used CTCAE v5 with incorporation of ASTCT consensus definitions for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Dose-limiting toxicities (DLTs) included &amp;gt; grade 3 CRS, &amp;gt; grade 3 ICANS, and persistent &amp;gt; grade 3 non-hematologic toxicity that did not resolve &amp;lt; grade 2 in 72 hours. CD33CART persistence was assessed via flow cytometric evaluation of the blood and bone marrow. Data cut-off was June 1, 2023. Results: A total of 24 subjects (median age of 16 years, range 1-34 years), were enrolled, 12 (50%) of whom underwent a prior SCT. CD33CART products were successfully manufactured for 23 subjects and infused into 19. In 4 non-infused subjects with manufactured products, 1 died from progressive disease (PD) prior to LD, 2 transitioned to palliative care and 1 withdrew consent to seek alternative therapy. Manufacturing was not performed in one subject due to death from PD after enrollment. One morbidly obese subject (BMI=49.3) enrolled at DL4 but received treatment at DL3 due to weight-based manufacturing limitations. The median time from enrollment to infusion was 47 days (range, 24-242). (Table) Three subjects each were infused at DL1 and DL2 without DLTs. At DL3, 1 subject experienced DLT (grade 4 CRS) prompting expansion at this dose level, and no subsequent DLTs were observed. At DL4, 1 subject experienced a prolonged grade 3 CRS (&amp;gt; 72 hours) and grade 3 ICANS, both constituting DLT and necessitating expansion of the cohort without additional DLTs seen. Across all dose-levels, CRS was seen in 13 (68%) patients and was &amp;gt; grade 3 in 4 (21%) with onset typically within the first 24 hours post-infusion. Complete remission (CR) was only seen at DL4 and achieved in 2 subjects, both achieving an MRD negative CR alongside myeloid aplasia. One SCT naïve subject developed candidemia during aplasia but was able to proceed to an allogenic SCT, achieved engraftment, and was in remission at Day +100 post SCT. The second patient (post-two prior SCTs) declined third SCT, had spontaneous count recovery and remained in remission until day +119 (MRD+ relapse). Transient CD33CART expansion was detected in 9 (47.4%) subjects overall and in all 6 (100%) subjects at DL4. Conclusions: CD33CART manufacturing is feasible in children and AYAs with r/r AML with acceptable toxicity experienced in treated subjects. CD33CART expansion was best in subjects treated at DL4 (1 x 10 7/kg) with MRD negative CRs and transient myeloid aplasia occurring in 2 of 5 (40%) subjects evaluable for response (Table). Based on early clinical efficacy at DL4, enrollment continues in the phase 2 portion.

Phase I Study of Bortezomib, Fludarabine, and Melphalan, with or without Total Marrow Irradiation as Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk or Relapsed/Refractory Multiple Myeloma

Though outcomes of patients with multiple myeloma (MM) have improved, cure remains elusive. Allogeneic hematopoietic stem cell transplantation (allo-sCT) is associated with a lower relapse rate, but its role is hindered due to toxicities. We hypothesized that targeted total body irradiation in the form of total marrow irradiation (TMI) could safely facilitate allo-SCT via an improved toxicity profile. Therefore, we conducted a phase I study to investigate the safety and feasibility of a bortezomib (BTZ), fludarabine (FLU), and melphalan (MEL), with or without TMI, prior to allo-SCT for patients with high-risk (HR) or relapsed/refractory (R/R) MM. Between 2012 and 2018 this study enrolled patients with HR or R/R MM on one of two strata, each comprising BTZ dose-escalation cohorts. Patients aged 18-60 with no prior radiation (RT) received TMI at 900 cGy (in 6 fractions delivered twice-daily), FLU, and MEL conditioning, with BTZ added in the second cohort (stratum I). Patients aged 18-70 with prior RT received FLU, MEL, and BTZ, without TMI (stratum II). The primary endpoint was feasibility of escalating doses of BTZ, with or without TMI, defined using a 3+3 design. Dose-limiting toxicity (DLT) was defined as any Grade 3+ Bearman toxicity or prolonged CTCAE v4.0 Grade 4+ neutropenia. Secondary endpoints included treatment response, time to neutrophil and platelet engraftment, incidence of acute (a) and chronic (c) graft-versus-host disease (GVHD), progression-free-survival (PFS), and overall survival (OS). Eight patients were enrolled on stratum I. One of three patients in the first cohort of stratum I experienced DLT, which led to expansion to three more patients with no DLT. Cohort 2 enrolled only 2 patients due to low accrual, with BTZ added at 0.5 mg/m2; neither experienced DLT. Nine patients were enrolled on stratum II. Three patients were enrolled on cohort 1 (BTZ 0.5 mg/m2) and none experienced DLT. Three were enrolled on cohort 2 (bortezomib 0.7 mg/m2), and one experienced DLT. Therefore, the cohort expanded to three more patients. One more patient experienced DLT and 0.5 mg/m2 was considered the maximum tolerated dose. There were no primary or secondary graft failures. Complete response was achieved in 7 and 4 patients in strata I and II, respectively. Median follow-up for all patients was 30.7 months (mos) and was 99.8 mos for surviving patients. Median overall survival (OS) on strata I and II were 44.5 mos and 21.6 mos, respectively. Median PFS on strata I and II were 18.1 mos and 8.9 mos, respectively. In strata I, 5 patients developed Grade 2+ aGVHD and 8 developed extensive cGVHD. In strata II, 4 patients developed Grade 2+ aGVHD and 6 developed extensive cGVHD. The TMI 900 cGy, FLU, and MEL conditioning regimen is considered safe as conditioning for allo-SCT and may warrant further investigation due to favorable response rates and survival; the conditioning regimen of FLU, MEL, and BTZ (0.7 mg/m2) is associated with unacceptable toxicities.