A clinical dose-finding study to assess the safety and efficacy of gene-modified T cells in patients with high risk blood tumors

Phase 1

• Conditions: High Risk Myeloid Neoplasms; MedDRA version: 21.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: HLTClassification code 10028536Term: Myelodysplastic syndromesSystem Organ Class: 100000004851; MedDRA version: 21.0Level: LLTClassification code 10028557Term: Myeloid leukemia, acuteSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: PTClassification code 10028533Term: Myelodysplastic syndromeSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-000440-18-DE
• Lead Sponsor: Medigene AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-07-12
• Last Update Posted: 8 August 2022

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 92

Inclusion Criteria

Key inclusion criteria include:
1. Signed written informed consent prior to any clinical trial related activities
2. Documented diagnosis with the last disease staging within the last 4 weeks prior to screening
3. Human leukocyte antigen (HLA)
a. Phase I and Phase II (treatment group): Subjects positive for HLA-A*02:01 according to genotyping results
b. Phase II (concurrent control group): Subjects negative for HLA-A*02:01 according to genotyping results
4. Age = 18 years
5. Life expectancy of at least 4 months.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
7. Subjects not planned for allogeneic hematopoetic stem cell transplantation (HSCT) (e.g. based on disease characteristics or subject characteristics). Bridging to an allogeneic HSCT will be allowed.
8. Negative pregnancy test in women of childbearing potential (before leukapheresis and before administration of lymphodepleting chemotherapy).
9. For fertile men and women, agreement to use effective contraceptive methods during the clinical trial.

Acute Myeloid Leukemia (AML)-specific inclusion criteria:
1. No complete remission response (CR) or no complete remission with incomplete heamatologic recovery (CRi) after completion of at least 2 cycles of intensive induction chemotherapy or 1 cycle of intensive induction and consolidation (intermediate or high dose cytarabine chemotherapy),
and/or
2. No CR or no CRi after completion of at least 1 cycle of intensive induction chemotherapy including at least 5 days of cytarabine 100-200 mg/m² continuously or an equivalent regimen with cytarabine with total dose not less than 500 mg/m² per cycle and at least 2 days of an anthracycline (e.g. daunorubicin, idarubicin), unable to undergo allogeneic HSCT
and/or
3. Refractory disease (including stable disease [SD], progressive disease [PD]) or relapsed disease after hypomethylating agent therapy (e.g. azacitidine, decitabine),
and/or
4. Any SD, partial reponse (PR), CRi, CR obtained after re-induction or salvage therapy,
and/or
5. Relapsed AML patients unable to undergo allogeneic HSCT,
and/or
6. Relapsed AML after allogeneic HSCT;
a. at least 100 days after transplant.
b. no evidence of active acute or chronic GvHD at enrolment, in case of history of acute (> overall grade 1) or chronic GvHD (moderate/severe) requiring immunosuppressive treatment no immunosuppression within the last 3 months,
c. no immunosuppression (with the exception of low-dose steroids =10 mg prednisone or equivalent) 4 weeks before enrollment and ongoing,
and
7. Myeloid blasts must positively express PRAME

Myelodysplastic Syndrome (MDS)-specific inclusion criteria:
1. International Prognostic Scoring System Intermediate-2 (IPSS INT-2) or High Grade MDS EB-2, not responding to at least 6 courses of azacitidine or 4 courses of decitabine and/or
2. IPSS INT-1, INT-2 or High Grade MDS with recurrence after initial response and
3. Blasts must positively express PRAME

Criteria for pre-emptive leukapheresis procedure:
• subject is positive for HLA-A*02:01 and their blasts/myeloma cells express PRAME,
• subject fulfills at least some inclusion criteria and, based on the judgement of the investigator, have a likelihood of being eligible for IMP administration in the further course of the subjects disease,
• subject does not fulfill any exclusion criterion that would be considered permanent (i.e. irreversible organ function impairment) and therefore would certainly preclude the subject from receiving

Exclusion Criteria

Key exclusion criteria include:
1. Subjects with acute promyelocytic leukemia exhibiting t(15;17)(q22;q12); Promyelocytic Leukemia/Retinoic Acid Receptor Alpha (PML-RARA), or with variant translocations
2. Pregnant or lactating women
3. Known positive for human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
4. Any clinically significant, advanced or unstable disease or inadequate main organ function that may put the subjects at special risk, such as:
a. Creatinine > 2.0 times the upper normal serum level
b. total bilirubin, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) > 3.0 times the upper normal serum level
c. cardiac left ventricular ejection fraction < 40% at rest
d. severe restrictive or obstructive lung disease
5. History of haploidentical allogeneic stem cell transplantation
6. Subjects both with urinary outflow obstructions and on dialysis or subjects for whom cyclophosphamide is contraindicated for other reasons
7. Clinical significant and ongoing immune suppression including, but not limited to: immunosuppressive agents such as cyclosporine or corticosteroids (at an equivalent dose of =10 mg prednisone per day). Inhaled steroid and physiological replacement for adrenal insufficiency is allowed.
8. Subjects with currently active autoimmune disease
9. Subjects with a history of primary immunodeficiency
10. Subjects with a currently active second malignancy other than non-melanoma skin cancers or subjects with history of prior malignancy and previously treated with a curative intent therapy less than 1 year ago
11. Known or suspected hypersensitivity or intolerance to IMP, Cyclophosphamide, Fludarabine and/or tocilizumab or to any of the excipients
12. Participation in any clinical trial < 60 days prior to first IMP administration in case of antibodies and < 14 days for all other IMPs
13. Vulnerable subjects and/or subjects unwilling or unable to comply with procedures required in this clinical trial protocol

Exclusion Criteria for treatment with IMP in Phase I and Phase II (treatment group):
1. Uncontrolled central nervous system (CNS) disease
2. Uncontrolled infections or uncontrolled disseminated intravascular coagulation; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule
3. Ongoing = 3 grade cardiac, renal, pulmonary, gastrointestinal or hepatic toxicities according to National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule
4. Evidence of acute or chronic GvHD

Treatment Exemption Criterion:
Unable to generate IMP for infusion; however, if a lower than planned number of cells is available (at least 1 x 105 T cells/kg), the subject in Phase I/II of the clinical trial will have the option to receive IMP and will be analyzed in the safety and full analysis set populations.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified