Single Agent JNJ-56022473 in MDS and AML Patients FAILING HYPOMETHYLATING AGENT BASED THERAPY

NCT02992860 | Terminated Phase 2 DMC

• 2 other identifiers: SAMBA-trial11274
• Study Type: interventional
• Target: 25
• Locations: 2 countries
• Sites: 10

Brief Summary

The outcome of HMA-refractory patients with MDS or AML is dismal with a median survival of 5 months after failure, representing a significant unmet medical need due to the very limited treatment options. In this context, a specific targeting of the leukemic stem cell (LSC) seems a promising option to selectively combat the leukemic progenitor cells. In fact, CD123 is overexpressed in AML and MDS progenitors making it an attractive target for immunotherapy-based approaches. JNJ-56022473 is a promising compound that has been engineered with regard to this strategy and the current phase II trial has the aim to evaluate the overall hematological response rate at 3 months in HMA refractory/relapsed AML and MDS patients.

Conditions

Myelodysplastic Syndrome (MDS); Acute Myeloid Leukemia (AML)

Keywords

Myelodysplastic Syndrome (MDS); Acute Myeloid Leukemia (AML); hypomethylating agent (HMA) treatment; leukemic stem cell; CD123; immunotherapy

Outcome Measures

Primary Outcomes (1)

• Overall hematological response rate

  Overall hematological response rate at 3 months (either CR, PR, marrow-CR, HI, SD)

  3 months

Secondary Outcomes (7)

• Toxicity

  3 or 12 months

• Overall survival

  1 year

• Progression-free-survival

  1 year

• Overall hematological response rate at 12 months

  1 year

• Quality of life EORTC-QLQ30

  9 or 15 months

Study Arms (1)

Treatment Arm

EXPERIMENTAL

JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.

Drug: JNJ-56022473; Procedure: Bone marrow analyses and CBC with differential; Other: Flow cytometry analyses; Other: Central biobanking; Procedure: Histopathology analysis; Genetic: Cytogenetic analysis; Procedure: Serum chemistry; Procedure: Automated CBC; Procedure: Pregnancy Test

Interventions

JNJ-56022473 DRUG

JNJ-56022473 will be supplied as a lyophilized product containing 100mg of active pharmaceutical ingredient (50 mg/mL after reconstitution with 2.0 mL sterile water for injection). The JNJ-56022473 dose administered will be dependent upon the subject's weight at baseline. The JNJ-56022473 dose should be adjusted in case the subject's weight changes by \> 10%. JNJ- 56022473 will be administered in 250 mL IV infusion over approximately 180 minutes using an infusion pump.

Also known as: CSL362

Treatment Arm

Bone marrow analyses and CBC with differential PROCEDURE

Bone marrow analyses and CBC with differential will be performed by a central laboratory. If the marrow cannot be aspirated, a biopsy should be performed.

Treatment Arm

Flow cytometry analyses OTHER

Characterization of LSCs and blasts (including CD123 and CD38 expression) will be performed as study-related analyses in the context of this protocol by central flow cytometry using bone marrow samples.

Treatment Arm

Central biobanking OTHER

Central biobanking of study samples (bone marrow, peripheral blood as well as a buccal swab) will be carried out in Dresden.

Treatment Arm

Histopathology analysis PROCEDURE

A bone marrow biopsy is taken whenever it seems necessary to the investigator.

Treatment Arm

Cytogenetic analysis GENETIC

The cytogenetic analysis with banding analysis (optional FISH) have to be performed at local labs. Therefore 2 - 5 ml of bone marrow will be collected and analysed.

Treatment Arm

Serum chemistry PROCEDURE

For serum chemistry 15 ml (2 x 7,5 ml) of peripheral blood have to be collected.

Treatment Arm

Automated CBC PROCEDURE

For CBC a minimum of 3 ml of peripheral blood have to be collected.

Treatment Arm

Pregnancy Test PROCEDURE

Serum or urine pregnancy testing β-HCG with a sensitivity of at least 25 mIU/mL is to be done not more than 3 days prior to initiation of JNJ-56022473 in female patients with childbearing potential. Furthermore, serum or urine pregnancy testing has to be done after end of treatment (EoT) visit.

Treatment Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥18 years of age
• Diagnosis of AML or MDS
• At least ≥ 5% BM blasts at the time of screening (done by central morphology)
• At least one cytopenia (ANC \< 1800/μL or platelet count \< 100,000/μL or hemoglobin \< 10 g/dL)
• Failure to achieve complete or partial response or hematological improvement after at least six (azacitidine) or four (decitabine) 4-week treatment cycles administered during the past two years OR
• Relapse after initial complete or partial response or hematological improvement observed after at least six (azacitidine) or four (decitabine) 4-week treatment cycles administered during the past two years OR
• Intolerance to treatment with HMA (hypomethylating agents) defined by drug-related ≥ Grade 3 liver or renal toxicity leading to treatment discontinuation during the past two years
• Failed to respond to, relapsed following, not eligible, or opted not to participate in bone marrow transplantation
• Off all other treatments for AML/MDS for at least four weeks; Filgrastim (G-CSF) and erythropoietin are allowed before and during the study as clinically indicated
• No medical need for or patient opted not to receive induction chemotherapy
• ECOG performance status of 0-2
• Willing to adhere to the prohibitions and restrictions specified in the protocol
• Signed informed consent

You may not qualify if:

• Previous treatment with a CD123 agent or T- or NK cell redirecting therapy
• Patients having received intensive chemotherapy to treat HMA failure
• Diagnosis of acute promyelocytic leukemia (APL)
• WBC \> 15 GPT/L
• Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
• Active infection not adequately responding to appropriate therapy
• Total bilirubin \> 1.5 mg/dL not related to hemolysis or Gilbert's disease
• ALT/AST \> 2.5 x upper limit of normal
• Serum creatinine \> 2.0 mg/dL
• Patients who are unwilling to follow highly effective contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives, contraceptive injections, intrauterine device, , contraceptive patch, surgical sterilization or true sexual abstinence) before entry, at least at screening, throughout the study and within 3 months after last study drug administration
• Female patients with reproductive potential who do not have a negative urine β-HCG pregnancy test at screening and prior to the first study drug administration at visit 1 (day 0) of JNJ-56022473 treatment period.
• Female patients who are lactating

Sponsors & Collaborators

• GWT-TUD GmbH: lead

Study Sites (10)

CHU Nantes

Nantes, France

Location

Hospital Archet 1

Nice, France

Location

Hospital Saint Louis

Paris, France

Location

CHU Toulouse

Toulouse, France

Location

Klinikum Chemnitz gGmbH, Klinik für innere Medizin III

Chemnitz, Germany

Location

Universitätsklinikum Dresden

Dresden, Germany

Location

Heinrich Heine Universität

Düsseldorf, Germany

Location

Marien Hospital GmbH

Düsseldorf, Germany

Location

Technische Universität München, Klinikum rechts der Isar

Munich, Germany

Location

Universitätsklinikum Ulm

Ulm, Germany

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myeloid, Acute

Interventions

Blood Cell Count; Cytogenetic Analysis; Pregnancy Tests

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Cell Count; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Hematologic Tests; Investigative Techniques; Cell Physiological Phenomena; Blood Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena; Genetic Techniques; Diagnostic Techniques, Obstetrical and Gynecological

Study Officials

• Uwe Platzbecker, Prof.

  Universitätsklinikum Dresden

  PRINCIPAL INVESTIGATOR

• Lionel Adés, Dr.

  Hospital Saint Louis Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2016
• First Posted: December 14, 2016
• Study Start: July 1, 2016
• Primary Completion: October 1, 2018
• Study Completion: October 1, 2018
• Last Updated: October 25, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share

Locations

FR (4); DE (6)