Clinical trial NCT04988555: A Study of DSP-5336 in Relapsed/Refractory AML/ ALL With or Without MLL Rearrangement or NPM1 Mutation
Official title: A Phase 1/2, Open-Label, Dose-Escalation, Dose-Expansion Study of DSP-5336 in Adult Patients With Acute Leukemia and Other Selected Hematologic Malignancies, With and Without Mixed Lineage Leukemia (MLL) Rearrangement or Nucleophosmin 1 (NPM1) Mutation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Leukemia, Myeloid, Acute
Leukemia, Lymphocytic, Acute
Keywords: Relapsed or refractory AML
MLLr
Menin
NPM1m
KMT2A
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2021-08-03
Enrollment: 362
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Bayesian Regression Model for Phase 1 dose escalation
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

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):

1. 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)
2. 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):

1. 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
2. Have measurable disease as defined in the protocol
3. 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):

1. Have MLLr or NPM1m.

   For patients with relapsed/refractory AML in the gilteritinib combination cohort (in countries and sites where permitted):
2. 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.

1. Patients must not have had prior exposure to a menin inhibitor
2. 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.
3. 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.
4. 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.
5. ECOG \< 2; For Phase 2 only, patients must have an ECOG performance status 0 or 1.
6. 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)
7. Clearance of creatinine (CLcr) level ≥ 50 ml/min, assessed by the Cockcroft-Gault formula
8. Total bilirubin ≤1.5 the upper limit of normal (ULN) (or ≤2.0 ULN for patients with known Gilbert's syndrome)
9. Aspartate aminotransferase (AST) ≤3.0 times ULN
10. Alanine aminotransferase (ALT) ≤3.0 times ULN
11. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia or neuropathy.
12. Be willing to attend study visits as required by the protocol
13. Have an estimated life expectancy ≥3 months, based on the investigator's assessment
14. Females of childbearing potential must have a negative serum pregnancy test.
15. 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.
16. 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.

Exclusion Criteria:

1. Has a left ventricular ejection fraction (LVEF) \<50%, as determined by ECHO
2. Histological diagnosis of acute promyelocytic leukemia
3. Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
4. 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.
5. 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.
6. 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.
7. Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within 42 days prior to the first dose of DSP-5336
8. Had major surgery within 28 days prior to the first dose of DSP-5336
9. Has active central nervous system leukemia. Patients with a history of any CNS leukemia involvement are excluded from Phase 2 Arms G and H.
10. 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.
11. 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
12. 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
13. 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
14. 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.
15. 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
16. 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
17. 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
18. 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.
19. Have a history of Torsades de Pointes
20. Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP-5336
21. Have plasma cell leukemia (\>2.0 x 109 /L plasma cells in blood by standard differential) (for patients with MM only)
22. 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)
23. Have a known intolerance of hypersensitivity reaction to components of the investigational medicinal product
24. Patients with LDH \>500 U/L (\>8.3 µkat/L) are excluded from Phase 2 Arms G and H

Primary outcomes:
measure: Phase I Assess the safety and tolerability of DSP-5336 in relapsed/refractory AML, ALL or acute leukemia of ambiguous lineage
timeFrame: Approximately 2 months after first dose
measure: 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.
timeFrame: Approximately 2 months after first dose
measure: 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)
timeFrame: Approximately 6 months after first dose
Secondary outcomes:
measure: Phase I Preliminary clinical activity of DSP-5336 in adult patients with AML or ALL
timeFrame: Approximately 6 months after first dose
measure: 2. Phase 2 To further assess safety and tolerability of DSP-5336 in adult patients with Relapsed /refractory AML
timeFrame: Approximately 2 months after first dose
Other outcomes:
Locations:
city: Newport Beach
country: United States
facility: Hoag Family Cancer Center
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Chicago
country: United States
facility: Northwestern
state: Illinois
city: Baltimore
country: United States
facility: Sibley Memorial Hospital
state: Maryland
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Main Center
state: Maryland
city: Boston
country: United States
facility: Tufts University
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Morristown
country: United States
facility: Atlantic Health
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: UNC Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Atrium Wake Forest Baptist Medical Center
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Eugene
country: United States
facility: Oncology Associates of Oregon
state: Oregon
city: Philadelphia
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center
state: Pennsylvania
city: Pittsburg
country: United States
facility: Allegheny Health Network
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: TriStar Centennial Medical Center
state: Tennessee
city: Houston
country: United States
facility: MDACC
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Salt Lake City
country: United States
facility: Intermountain Healthcare
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Antwerpen
country: Belgium
facility: ZNA Cadix
city: Ghent
country: Belgium
facility: UZ Ghent
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Roeselare
country: Belgium
facility: AZ Delta
city: Calgary
country: Canada
facility: Tom Baker Cancer Center
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
city: Angers
country: France
facility: Centre Hospitalier Universitaire d'Angers
city: Bobigny
country: France
facility: Hopital Avicenne
city: Le Mans
country: France
facility: Centre Hospitalier Le Mans
city: Lille
country: France
facility: Hopital Claude Huriez
city: Limoges
country: France
facility: Centre Hospitalier Universitaire de Limoges
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Nice
country: France
facility: CHU de Nice - Hôpital l'Archet 1
city: Paris
country: France
facility: Hopital Saint-Louis
city: Talence
country: France
facility: CHU Bordeaux
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Bologna
country: Italy
facility: Alma Mater Studiorum University Of Bologna
city: Genoa
country: Italy
facility: Ospedale Policlinico San Martino, IRCCS
city: Meldola
country: Italy
facility: IRCCS istituto Romagnolo per lo studio dei tumori "Dino Amadori"
city: Padua
country: Italy
facility: Istituto Oncologico Veneto (IOV), IRCCS
city: Perugia
country: Italy
facility: Università degli Studi di Perugia
city: Rome
country: Italy
facility: PU A. Gemelli, Università Cattolica del Sacro Cuore
city: Turin
country: Italy
facility: Universita' Degli Studi Di Torino
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Yoshida-gun
country: Japan
facility: University of Fukui Hospital
state: Fukui
city: Fukushima-shi
country: Japan
facility: Fukushima Medical University Hospital
state: Fukushima
city: Isehara-shi
country: Japan
facility: Tokai University Hospital
state: Kanagawa
city: Nagasaki-shi
country: Japan
facility: Nagasaki University Hospital
state: Nagasaki
city: Bunkyo-ku
country: Japan
facility: Nippon Medical School Hospital
state: Tokyo
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Hokkaido
country: Japan
facility: Hokkaido University Hospital
city: Miyagi
country: Japan
facility: Tohoku University Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Hwasun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea
city: Singapore
country: Singapore
facility: National University Cancer Institute
city: Albacete
country: Spain
facility: Hospital General Universitario De Albacete
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D'Hebron
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia
city: Cantabria
country: Spain
facility: Fundacion Instituto de Investigacion Marques de Valdecilla
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Las Palmas
country: Spain
facility: Hospital Universitario De Gran Canaria Dr. Negrin
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Oviedo
country: Spain
facility: Hospital Universitario Central De Asturias
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santiago de Compostela
country: Spain
facility: Complexo Hospitalario Universitario De Santiago
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico La Fe
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan City
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Birmingham
country: United Kingdom
facility: University Hospitals of Birmingham Centre for Clinical Hematology
city: Bristol
country: United Kingdom
facility: Bristol Hematology & Oncology Centre
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Christie Hospital NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Churchill Hospital Oxford
city: Stoke-on-Trent
country: United Kingdom
facility: University Hospitals of North Midlands NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
References: