A Study of DSP-5336 in Relapsed/Refractory AML/ ALL With or Without MLL Rearrangement or NPM1 Mutation
- Conditions
- Leukemia, Myeloid, AcuteLeukemia, Lymphocytic, Acute
- Interventions
- Registration Number
- NCT04988555
- Lead Sponsor
- Sumitomo Pharma America, Inc.
- Brief Summary
A phase 1/2 dose escalation / dose expansion study of Enzomenib (DSP-5336) in adult patients with acute leukemia.
- Detailed Description
Phase 1 (dose escalation) will determine the recommended Phase 2 dose (RP2D) (i.e. the lowest dose of Enzomenib (DSP-5336), that provides the maximum biologic and clinical effect, or the MTD, whichever is lower) in adult patients with relapsed or refractory AML, ALL, or acute leukemia of ambiguous lineage. Enrollment to the phase 1 portion of the study may be limited to patients with certain genetic abnormalities.
Phase 2 dose-expansion will further evaluate the safety and clinical activity of Enzomenib (DSP-5336) monotherapy in patients with relapsed/refractory AML who have MLLr or NPM1m, and relapsed/refractory ALL who have MLLr.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 362
Patients in the Phase 1 dose-escalation portion must have a diagnosis of relapsed or refractory AML, ALL or acute leukemia of ambiguous lineage according to World Health Organization (WHO) 2022 classification, or, in the US only, a diagnosis of MDS or MM as determined by pathology review at the treating institution, and whose disease has progressed after available standard therapies known to be active for their AML, ALL, or acute leukemia of ambiguous lineage or, in the US, for MM or MDS.
For patients with MDS (US only):
- Patients with MDS must have IPSS-R risk categorization of "high" or "very high" at initial diagnosis or at study entry and have bone marrow blasts ≥ 5% (which is the definition of high-risk MDS in this study)
- Patients with MDS must have relapsed or refractory disease and have exhausted available standard therapies including at least 2 cycles of treatment with HMA
For patients with MM (US only):
- Have a confirmed diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) 2016 classification (Kumar, 2016) and whose disease has progressed after treatment with a minimum of 3 prior anti-myeloma regimens including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb); patients must not be candidates for available therapies with established clinical benefit
- Have measurable disease as defined in the protocol
- Meet the laboratory parameters set in the protocol
For patients with relapsed/refractory AML in the venetoclax and azacitidine combination cohort (in countries and sites where permitted):
-
Have MLLr or NPM1m.
For patients with relapsed/refractory AML in the gilteritinib combination cohort (in countries and sites where permitted):
-
Have MLLr or NPM1m AND any of the following FLT3 mutations: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.
Patients in the Phase 2 dose expansion portion of the study must have a confirmed diagnosis of relapsed AML or ALL as determined by pathology review at the treating institution, and who have ≥5% blasts by morphologic assessment in the bone marrow and failed available standard therapies known to be active for their AML (Arm G and H) or ALL (Arm I). If the primary disease is a transformation from MDS or other hematologic malignancies, patients need to receive available standard therapies for acute leukemia before enrolling this trial. Participants who are candidates for stem cell transplantation must have been offered this therapeutic option. Patients with extramedullary disease or peripheral blasts as the only manifestation of relapse are not eligible.
-
Patients must not have had prior exposure to a menin inhibitor
-
Patients for Arms G and H are limited to a total of 3 prior lines of therapy, with induction chemotherapy, consolidation chemotherapy, and stem cell transplantation with or without subsequent maintenance treatment considered to be 1 line.
-
Have a documented KMT2A (MLL)-fusion for Arm G and I or NPM1 mutation for Arm H assessed at relapse or immediately prior to the determination of refractory status. For Arms G and I, KMT2A genetic alterations other than fusions (eg, KMT2A-PTD, amplification, point mutation) are not permitted.
-
Be > 18 years of age. For countries and sites where approved, for DSP-5336 monotherapy, acute leukemia patients ≥12 years of age who weigh ≥40 kg may be enrolled.
-
ECOG < 2; For Phase 2 only, patients must have an ECOG performance status 0 or 1.
-
For monotherapy, WBC below 30,000/μ. For the combination arms, WBC count must be below 25,000/uL at enrollment and prior to starting treatment. (Hydroxyurea and steroids for cytoreduction purposes are allowed prior to enrollment and during study treatment)
-
Clearance of creatinine (CLcr) level ≥ 50 ml/min, assessed by the Cockcroft-Gault formula
-
Total bilirubin ≤1.5 the upper limit of normal (ULN) (or ≤2.0 ULN for patients with known Gilbert's syndrome)
-
Aspartate aminotransferase (AST) ≤3.0 times ULN
-
Alanine aminotransferase (ALT) ≤3.0 times ULN
-
Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia or neuropathy.
-
Be willing to attend study visits as required by the protocol
-
Have an estimated life expectancy ≥3 months, based on the investigator's assessment
-
Females of childbearing potential must have a negative serum pregnancy test.
-
Must agree to use a highly effective contraception method or 2 acceptable methods of birth control (each partner must use one method) or use prevention of pregnancy measures (ie, agreement to refrain completely from heterosexual intercourse) during the study and for 6 months (for females and males alike) after the last dose of study drug, if male or female patient is of child-producing potential
For sites in Japan only: Implantable hormonal contraceptives, a diaphragm with spermicide, cervical cap with spermicide and contraceptive sponge (spermicide is already in the contraceptive sponge) included in the barrier contraceptive method are not approved and cannot be used in Japan.
-
Have AML/ALL/MDS/MM bone marrow material suitable for genomic analysis of AML,ALL, MDS, or MM genetic alterations. Note: If a bone marrow material is insufficient, an alternative suitable tissue (ex: peripheral blood) must be provided.
-
Has a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
-
Histological diagnosis of acute promyelocytic leukemia
-
Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
-
Have abnormal ECGs at screening that are clinically significant, such as (QTc >480 msec, with QTc corrected according to Fridericia's formula (QTcF). Note: In case of bundle branch block, QT interval correction can be performed.
-
Has an active anduncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy. Note: Patients must be afebrile with negative blood cultures at least 72 hours prior to Cycle 1 Day 1.
-
Receives concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole, isavuconazole and itraconazole. Other antifungals that are used as standard of care to prevent or treat infections are permitted. If a patient is on one of the excluded azole class antifungals, he/she can be taken off or switched to a permitted azole 7 or more days prior to first dose, then the patient could be allowed on study (Arm B) with approval of the medical monitor.
-
Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within 42 days prior to the first dose of DSP-5336
-
Had major surgery within 28 days prior to the first dose of DSP-5336
-
Has active central nervous system leukemia. Patients with a history of any CNS leukemia involvement are excluded from Phase 2 Arms G and H.
-
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336. Patients who have received >1 prior HSCT are excluded from Phase 2 Arms G and H.
-
Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP-5336, or receiving immunosuppressive therapy post-HSCT at the time of screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD
-
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
-
In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results
-
Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of hepatitis B surface antigen, all being indicative of active infection.
For sites in Japan, Taiwan, and Korea only: Hepatitis B core (HBc) antibody or hepatitis B surface (HBs) antibody test should be performed if HBsAg is negative. If HBc antibody or HBs antibody test is positive, HBV DNA quantification test should be performed to confirm that HBV DNA is negative.
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Have severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication
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Have cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient o receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent process, protocol, or protocol-required visits and procedures
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Are pregnant or breastfeeding or planning to become pregnant. Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug
-
Have any history or complication of interstitial lung disease (for sites in Japan in Phase 1 dose escalation only).
For clinical sites in the EU, have a history of Grade ≥ 2 drug-induced interstitial lung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of starting study treatment.
-
Have a history of Torsades de Pointes
-
Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP-5336
-
Have plasma cell leukemia (>2.0 x 109 /L plasma cells in blood by standard differential) (for patients with MM only)
-
For patients intending to enroll into the combination cohort with gilteritinib: Patients must be gilteritinib-naïve or sensitive and have not received a FLT3 inhibitor in the relapsed refractory setting (prior FLT3 inhibitor in front line therapy is allowed)
-
Have a known intolerance of hypersensitivity reaction to components of the investigational medicinal product
-
Patients with LDH >500 U/L (>8.3 µkat/L) are excluded from Phase 2 Arms G and H
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 2 Arm A AML with MLL (KMT2A) gene rearrangements DSP-5336 Patients with R/R AML w/MLL (KMT2A) gene rearrangements Phase 1 Arm A without Antifungals DSP-5336 Patients not taking antifungals within 7 days of study entry Phase 1 Arm B with Antifungals DSP-5336 Patients receiving anti-fungals that are moderate to strong cytochrome CYP3A4/5 inhibitors (i.e. Posaconazole, voriconazole, fluconazole, or isavuconazonium (prodrug of isavuconazole). Phase 2 Arm B: AML with NPM1c mutations DSP-5336 Patients with R/R AML w/ NPM1c mutations Phase 1 - Arm A Enzomenib Patients not taking antifungals within 7 days of study entry Phase 1 - Arm B Enzomenib Patients receiving antifungals that are moderate to strong cytochrome CYP3A4/5 inhibitors (i.e. posaconazole, voriconazole, or fluconazole). Phase 1 - Arm B azoles Patients receiving antifungals that are moderate to strong cytochrome CYP3A4/5 inhibitors (i.e. posaconazole, voriconazole, or fluconazole). Phase 1 - Arm C Enzomenib Patients with MDS Phase 1 - Arm E Enzomenib Patients with AML Phase 1 - Arm E Venetoclax Patients with AML Phase 1 - Arm E Azacitidine (AZA) Patients with AML Phase 1 - Arm F Enzomenib Patients with AML Phase 1 - Arm F Gilteritinib Patients with AML Phase 2 - Arm G Enzomenib R/R AML with MLLr Phase 2 - Arm H Enzomenib R/R AML with NPM1m Phase 2 - Arm I Enzomenib R/R ALL with MLLr
- Primary Outcome Measures
Name Time Method Phase I Assess the safety and tolerability of DSP-5336 in relapsed/refractory AML, ALL or acute leukemia of ambiguous lineage Approximately 2 months after first dose Occurrence of DLTs and frequency, duration and severity of TEAEs and SAEs assessed by NCI CTCAE v 5.0
Phase I Determine the RP2D based on lowest dose of DSP-5336 that provides the maximum biologic and clinical effect, or the MTD, whichever is lower. Approximately 2 months after first dose Occurrence of DLTs and frequency, duration and severity of TEAEs and SAEs, plasma concentration-time profiles, changes in expression levels of biomarkers (gene expression levels).
Phase 2 To evaluate clinical activity of DSP-5336 in adult patients with Relapsed /refractory AML who have MLL (KRMa gene rearrangement or NPM1 gene mutation) Approximately 6 months after first dose Occurrence of CR(MRD-); CR; CRh; CRi; PR; MLFS; CR(MRD-) + CR; CR(MRD-) + CR + CRh; OR (=CR(MRD-) or CR or CRi or MLFS or PR); DOR; time to response; time to CR; TI; OS; EFS; RFS
- Secondary Outcome Measures
Name Time Method Phase I Preliminary clinical activity of DSP-5336 in adult patients with AML or ALL Approximately 6 months after first dose Disease response as assessed by ELN 2017 criteria
2. Phase 2 To further assess safety and tolerability of DSP-5336 in adult patients with Relapsed /refractory AML Approximately 2 months after first dose Frequency, duration, and severity of TEAEs and SAEs assessed by NCI CTCAE v 5.0
Trial Locations
- Locations (92)
Hoag Family Cancer Center
🇺🇸Newport Beach, California, United States
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
University of Miami
🇺🇸Miami, Florida, United States
Northwestern
🇺🇸Chicago, Illinois, United States
Sibley Memorial Hospital
🇺🇸Baltimore, Maryland, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Johns Hopkins Main Center
🇺🇸Baltimore, Maryland, United States
Tufts University
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Atlantic Health
🇺🇸Morristown, New Jersey, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Roswell Park Comprehensive Cancer Center
🇺🇸Buffalo, New York, United States
Mount Sinai Hospital
🇺🇸New York, New York, United States
Columbia University
🇺🇸New York, New York, United States
UNC Hospital
🇺🇸Chapel Hill, North Carolina, United States
Duke University
🇺🇸Durham, North Carolina, United States
Atrium Wake Forest Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States
The Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
Oncology Associates of Oregon
🇺🇸Eugene, Oregon, United States
Sidney Kimmel Comprehensive Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Allegheny Health Network
🇺🇸Pittsburg, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
TriStar Centennial Medical Center
🇺🇸Nashville, Tennessee, United States
MDACC
🇺🇸Houston, Texas, United States
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
UZ Ghent
🇧🇪Ghent, Belgium
University Hospitals Leuven
🇧🇪Leuven, Belgium
AZ Delta
🇧🇪Roeselare, Belgium
Tom Baker Cancer Center
🇨🇦Calgary, Alberta, Canada
Hopital Claude Huriez
🇫🇷Lille, France
Intermountain Healthcare
🇺🇸Salt Lake City, Utah, United States
University of Virginia
🇺🇸Charlottesville, Virginia, United States
ZNA Cadix
🇧🇪Antwerpen, Belgium
Virginia Cancer Specialists
🇺🇸Fairfax, Virginia, United States
Virginia Oncology Associates
🇺🇸Norfolk, Virginia, United States
University of Alberta
🇨🇦Edmonton, Canada
Centre Hospitalier Universitaire d'Angers
🇫🇷Angers, France
Hopital Avicenne
🇫🇷Bobigny, France
Centre Hospitalier Le Mans
🇫🇷Le Mans, France
Centre Hospitalier Universitaire de Limoges
🇫🇷Limoges, France
Hospices Civils de Lyon
🇫🇷Lyon, France
Institut Paoli-Calmettes
🇫🇷Marseille, France
CHU de Nice - Hôpital l'Archet 1
🇫🇷Nice, France
Hopital Saint-Louis
🇫🇷Paris, France
CHU Bordeaux
🇫🇷Talence, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Alma Mater Studiorum University Of Bologna
🇮🇹Bologna, Italy
Ospedale Policlinico San Martino, IRCCS
🇮🇹Genoa, Italy
IRCCS istituto Romagnolo per lo studio dei tumori "Dino Amadori"
🇮🇹Meldola, Italy
Istituto Oncologico Veneto (IOV), IRCCS
🇮🇹Padua, Italy
Università degli Studi di Perugia
🇮🇹Perugia, Italy
PU A. Gemelli, Università Cattolica del Sacro Cuore
🇮🇹Rome, Italy
Universita' Degli Studi Di Torino
🇮🇹Turin, Italy
National Cancer Center Hospital East
🇯🇵Kashiwa-shi, Chiba, Japan
University of Fukui Hospital
🇯🇵Yoshida-gun, Fukui, Japan
Fukushima Medical University Hospital
🇯🇵Fukushima-shi, Fukushima, Japan
Tokai University Hospital
🇯🇵Isehara-shi, Kanagawa, Japan
Nagasaki University Hospital
🇯🇵Nagasaki-shi, Nagasaki, Japan
Nippon Medical School Hospital
🇯🇵Bunkyo-ku, Tokyo, Japan
Kyushu University Hospital
🇯🇵Fukuoka, Japan
Hokkaido University Hospital
🇯🇵Hokkaido, Japan
Tohoku University Hospital
🇯🇵Miyagi, Japan
Okayama University Hospital
🇯🇵Okayama, Japan
Chonnam National University Hwasun Hospital
🇰🇷Hwasun, Korea, Republic of
The Catholic University of Korea
🇰🇷Seoul, Korea, Republic of
Hospital General Universitario De Albacete
🇪🇸Albacete, Spain
Hospital Universitari Vall D'Hebron
🇪🇸Barcelona, Spain
Institut Catala d'Oncologia
🇪🇸Barcelona, Spain
Osaka University Hospital
🇯🇵Osaka, Japan
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Fundacion Instituto de Investigacion Marques de Valdecilla
🇪🇸Cantabria, Spain
Hospital San Pedro de Alcantara
🇪🇸Cáceres, Spain
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
National University Cancer Institute
🇸🇬Singapore, Singapore
Hospital Universitario De Gran Canaria Dr. Negrin
🇪🇸Las Palmas, Spain
MD Anderson Cancer Center
🇪🇸Madrid, Spain
Hospital Universitario Central De Asturias
🇪🇸Oviedo, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Complexo Hospitalario Universitario De Santiago
🇪🇸Santiago de Compostela, Spain
Hospital Universitario y Politecnico La Fe
🇪🇸Valencia, Spain
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
National Cheng Kung University Hospital
🇨🇳Tainan City, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
University Hospitals of Birmingham Centre for Clinical Hematology
🇬🇧Birmingham, United Kingdom
Bristol Hematology & Oncology Centre
🇬🇧Bristol, United Kingdom
King's College Hospital
🇬🇧London, United Kingdom
Sarah Cannon Research Institute
🇬🇧London, United Kingdom
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
Christie Hospital NHS Foundation Trust
🇬🇧Manchester, United Kingdom
Churchill Hospital Oxford
🇬🇧Oxford, United Kingdom
University Hospitals of North Midlands NHS Foundation Trust
🇬🇧Stoke-on-Trent, United Kingdom
The Royal Marsden NHS Foundation Trust
🇬🇧Sutton, United Kingdom