Primary Objective: To assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER AML, as determined by the proportion of patients who achieve CR/CRhSecondary Objectives:To describe response rate, duration of response, event-free…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy based on CR/CRh rate:
Proportion of patients achieving a best response of CR (morphologic CR,
cytogenetic CR, molecular CR, or CRh per Interworking Group AML response
criteria.
Secondary outcome
Efficacy Endpoint:
response rate, duration of response, event-free survival, overall survival and
transplantation rate
Background summary
The Dual Affinity Re-Targeting (DART®) technology is a novel, bispecific
antibody platform designed to eradicate AML (or other tumor) cells through
co-engagement of a leukemia- or tumor-specific cell surface marker (e.g.,
CD123) and the T-cell receptor (TCR)/CD3 complex on T cells as effector cells.
Cell-association studies indicated that the DART protein architecture is well
suited for maintaining cell-to-cell contact, apparently contributing to the
high level of target cell killing. CD19 x TCR and CD19 x CD3 DART protein have
demonstrated in vitro killing of B-cell lymphomas by human T cells or
peripheral blood mononuclear cells (PBMCs) (14) that exceeds the killing
associated with a similar bispecific antibody construct, BiTE. The CD19 x TCR
DART protein has also been used in in vivo tumor models and has demonstrated
inhibition of B-cell lymphoma in NOD/SCID mice when co-administered with human
PBMCs.
Flotetuzumab, also known as S80880, is a novel CD123 x CD3 DART protein
developed by MacroGenics, Inc. Flotetuzumab is designed to target
CD123-positive cells (including AML cells) for recognition and elimination by
CD3-expressing T lymphocytes as effector cells.
Flotetuzumab shows potent activity to redirect T cell killing against
CD123-expressing cell lines and primary AML blasts in vitro. Flotetuzumab also
demonstrated inhibition of growth of leukemic cell lines in mice and depletion
of the CD123-positive pDC cells in the repeat-dose toxicology studies. The data
from the nonclinical studies provide strong scientific rationale that an
evaluation of the safety and potential activity of the CD123 x CD3 DART
protein, Flotetuzumab, in patients with AML whose disease is not expected to
benefit from additional cytotoxic chemotherapy (as specified below), is
warranted.
Study objective
Primary Objective:
To assess the anti-neoplastic activity of flotetuzumab in patients with PIF/ER
AML, as determined by the proportion of patients who achieve CR/CRh
Secondary Objectives:
To describe response rate, duration of response, event-free survival, overall
survival and transplantation rate.
Study design
This is an open-label, multi-dose, single-arm, multi-center, Phase 1/2,
dose-escalation and expansion study to define a MTDS; describe preliminarily
safety; and assess the PK, immunogenicity, immunomodulatory activity, and
potential anti-neoplastic activity of flotetuzumab in patients with AML and MDS
whose disease is not expected to benefit from cytotoxic chemotherapy.
This study is designed in three segments: the Single Patient Dose Escalation
Segment (completed), followed by the Multi-Patient Dose Escalation Segment
(completed) and the MTDS Expansion Cohort Segment (ongoing). Two expansion
cohorts were planned, one in AML and one in MDS. As of amendment 7, the sponsor
stopped enrolling patients with MDS into this study.
Intervention
See 'J: Aanvullende informatie'.
Study burden and risks
- Central line placement (for study drug infusions and drawing blood samples)
- Vital signs
- Electrocardiogram
- Physical examination
- Blood collection
- Urine collection
- Bone marrow aspirate/biopsies
- Treatment after Cycle 1 Day 8 may take place in the outpatient setting based
on patient's tolerance of therapy. The patient may also be required to be in
the hospital during the first 24 to 48 hours of Cycle 2 and any additional
infusions depending on the dosing schedule.
Medical Center Drive 9704
MD 20850 Rockville
US
Medical Center Drive 9704
MD 20850 Rockville
US
Listed location countries
Age
Inclusion criteria
1. Patients must have a confirmed diagnosis of primary or secondary AML (any
subtype except acute promyelocytic leukemia [APL]) according to World Health
Organization (WHO) classification.
2. Patients with AML must meet one of the following criteria:
a Primary Induction Failure (PIF) AML, defined as disease refractory to one of
the following:
- An intensive induction attempt, per institution. Induction attempts include
high dose and/or standard-dose cytarabine +/- an anthracyclines/anthracenedione
+/- and anti-metabolite, with or without growth factor or targeted therapy
containing regimes.
Examples include but are not limited to:
1. One cycle of high dose cytarabine (HiDAC) containing
regimen
2. One cycle of liposomal cytarabine and daunorubicin
3. Two cycles of standard dose cytarabine containing regimen
- For adults who are age 75 years or older, who have comorbidities that
preclude use of intensive induction chemotherapy; PIF is defined as AML
refractory to one of the following less intensive regimes, 1 or 2:
1. >= 2 but <= 4 cycles of Bcl-2 inhibitors in combination with
azacitidine, decitabine, or low dose cytarabine
2. >= 2 but <= 4 cycles of gemtuzumab ozogamicin monotherapy
b. Early Relapse (ER) AML, defined as AML in first relapse with initial CR 1
duration < 6 months.
3. Limit of 3 prior lines of therapy (excluding focal radiation therapy for
palliative purposes): up to 2 induction (induction, re-induction) or 1
induction plus/minus 1 consolidation attempt, followed by a maximum of 1
salvage/re-induction attempt.
4. Eastern Cooperative Oncology Group (ECOG) performance status less-than or
equal to 2.
5. Life expectancy of at least 4 weeks.
6. Peripheral blast count less-than or equal to 20,000/mm3 at the time of
first dose of study treatment (see related Exclusion Criterion 3).
7. Acceptable laboratory parameters and adequate organ reserve.
8. Adult: Eighteen (18) years of age or older.
Exclusion criteria
1. Prior history of allogeneic stem cell transplantation
2. Prior treatment with an anti-CD123-directed agent.
3. Need for concurrent other cytoreductive chemotherapy
4. Any active untreated autoimmune disorders (with the exception of vitiligo,
resolved childhood atopic dermatitis, prior Grave's disease now euthyroid
clinically and with stable supplementation)
5. Second primary malignancy that requires active therapy. Adjuvant hormonal
therapy is allowed.
6. Antitumor therapy or investigational agent within 14 days or 5 half-lives of
Cycle 1 Day 1.
7. Requirement, at the time of study entry, for concurrent steroids > 10 mg/day
of oral prednisone or the equivalent, except steroid inhaler, otic
preparations, nasal spray or ophthalmic solution
8. Use of immunosuppressant medications in the 2 weeks prior to study drug
administration (Cycle 1 Day 1)
9. Use of granulocyte colony stimulating or granulocyte-macrophage colony
stimulating factor in the 2 weeks prior to study drug administration (Cycle 1
Day 1)
10. Known central nervous system (CNS) leukemia.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003813-11-NL |
| ClinicalTrials.gov | NCT02152956 |
| CCMO | NL56485.042.16 |