An Open-Label Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal Doxorubicin for the Treatment of Patients with Relapsed/Refractory Acute Myelogenous Leukemia
Authors: Potter Laura A. , Galkin Maria , Rosenberg Aaron S. , Hoeg Rasmus T. , Abedi Mehrdad , Tuscano Joseph M. , Jonas Brian A. 
Published: November 2021

Abstract
Background
Relapsed/refractory (R/R) acute myeloid leukemia (AML) remains a challenge to cure. Prior studies of hypomethylating agent (HMA) decitabine (DEC), proteasome inhibitor bortezomib (BTZ), and anthracycline (AC) pegylated liposomal doxorubicin (PLD) monotherapy, as well as DEC + BTZ and BTZ + PLD regimens, have demonstrated safety and modest activity in R/R AML. Inhibition of NF-κB signaling by BTZ and DEC could prevent AC resistance resulting from NF-κB activity. Thus, we hypothesized that the DEC + BTZ + PLD (DBP) regimen would have activity in R/R AML.
Methods
We performed a phase II trial of DBP, with a safety lead-in cohort, in patients aged 18-90 with R/R AML. The original protocol called for 1-4 28-day (D) cycles of induction with intravenous (IV) DEC 20mg/m 2 on D1-10, subcutaneous (SQ) BTZ 1.3mg/m 2 on D1, 4, 8, and 11, and IV PLD 40mg/m 2 on D4. Dose-limiting toxicity (DLT) of grade 3 peripheral neuropathy (G3 PN) in the first 2 patients led to a revised schedule of BTZ on D5, 8, 12, and 15 and PLD on D12, eliminating simultaneous DBP dosing on any 1 day. Patients achieving a bone marrow blast count &lt;5% after any course of induction proceeded to the continuation regimen: 28-D cycles of DEC on D1-5, BTZ on D1 and 8, and PLD on D12. Treatment continued until progression, intolerance, bone marrow transplant (BMT), study withdrawal, or administration of 12 cycles. Patients reaching lifetime maximum AC exposure could remain on trial with PLD removed from their regimen. Primary endpoint was objective response rate (ORR), defined as complete remission (CR) + CR with incomplete hematological recovery (CRi) + partial remission. Response was based on International Working Group criteria and determined by blood count values between cycles. Secondary endpoints of overall and event-free survival (OS, EFS) were estimated by Kaplan-Meier method. Toxicity was monitored per Common Terminology Criteria for Adverse Events (AEs) v4.03.
Results
Ten patients were enrolled from May 2016 to February 2018, after which the sponsor closed the protocol. Median age was 57 years [range 27-69]. Patients were 50% female, 60% White, 10% African American/Black, 30% other/mixed race, and 40% Hispanic/Latino, with median baseline ECOG score of 1 [0-1] and median 2 [1-3] lines of prior therapy. Sixty percent had de novo and 40% had secondary disease. By WHO subtype, 30% had AML with MRC, 20% NPM1 mutation, 10% inv(3), 10% therapy-related, and 30% not otherwise specified. European LeukemiaNet 2017 risk was favorable in 20%, intermediate in 40%, and adverse in 40%.
Median number of cycles completed was 2 [1-7] with a median time on study of 100.5 days [35-678]. One patient achieved CR and 2 achieved CRi for an ORR of 30%. An additional patient likely had a CR with &lt;5% blasts and count recovery but had a suboptimal aspirate differential. Including this unconfirmed CR, ORR was 40%. An additional 2 (20%) achieved morphological leukemia-free state (MLFS). Of the 6 patients with any response (CR + CRi + MLFS), 2 achieved best response after cycle 1, 2 after cycle 2, 1 after cycle 3, and 1 after cycle 4. Relapse occurred in 2 of 5 (40%) while on study, at 425 days after CRi and 83 days after MLFS. All 3 patients with prior HMA exposure were non-responders.
All patients discontinued treatment. Reasons included BMT (40%), AE (30%), progression (20%) and insurance loss (10%). Half planned to bridge to BMT as next-line therapy following study treatment. When taken off study, 50% were alive while 20% had died from AML complications, 20% from graft-versus-host-disease post-BMT, and 10% after relapse post-BMT. Median OS was 6.67 months (95% confidence interval [CI] 6.07 to not reached [NR]). Median EFS was 3.22 months (95% CI 1.50 to NR), with a maximum EFS of 16.93 months.
Following G3 PN in the first 2 patients, no DLTs occurred on the modified regimen. Seventy percent of patients experienced at least possibly related G3+ AEs or serious AEs (SAEs). Of the 22 related G3+ AEs, anemia and decreased platelet count were seen in 50% and dizziness in 20%. Of the 22 related SAEs, anorexia, fatigue, PN, febrile neutropenia, and bacteremia were most common, each occurring in 20%.
Conclusion
The DBP triplet demonstrated preliminary anti-AML activity in a R/R AML patient cohort. Staggered dosing was better tolerated than simultaneous DBP. DBP may serve as an effective bridge to BMT for some patients. This study supports further evaluation of DBP, or related combinations, in R/R AML.

Disclosures
Rosenberg: Takeda, Janssen: Speakers Bureau. Abedi: Seattle Genetics: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau. Tuscano: BMS, Seattle Genetics, Takeda, Achrotech, Genentech, Pharmacyclics, Abbvie: Research Funding. Jonas: AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement.

OffLabel Disclosure:
Bortezomib is FDA-approved for the treatment of multiple myeloma in patients who have already been treated with 2 lines of prior therapy and progressed on the most recent therapy. Decitabine is indicated for treatment of patients with myelodysplastic syndromes. Doxorubicin is approved in AML among other cancers.