| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute myeloid leukemia and Multiple myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute myeloid leukemia and multiple myeloma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I:
1. To determine the maximum tolerated dose (MTD) and recommended phase IIa dose of MLM-CAR44.1 T-cells in patients with relapsed/refractory acute myeloid leukemia (AML) or multiple myeloma (MM) expressing CD44v6.
2. To evaluate the overall safety of treatment with MLM-CAR44.1 T-cells.
Phase IIa:
To evaluate hematological response to MLM-CAR44.1 T-cells in AML and MM. |
|
| E.2.2 | Secondary objectives of the trial |
Phase I:
1. To evaluate hematological response to MLM-CAR44.1 T-cells in AML and MM.
2. To characterize the in vivo pharmacokinetic profile (engraftment, persistence, trafficking) of MLM-CAR44.1 T-cells.
3. To assess suicide gene activation and elimination of transduced cells through administration of ganciclovir in case of cytokine release syndrome (CRS) or other MLM-CAR44.1 T-cell related toxicities.
4. To conduct an ancillary study, including but not limited to the characterization of the cellular composition of circulating LNGFR+ (CAR T-cells) and LNGFR- cells, and the monitoring of the patient’s immune status through analyses of peripheral blood mononuclear cells (PBMC).
5. To set-up a validation process among the participating centers for the CD44v6 marking of tumor cells (AML and MM).
Phase IIa:
1. To evaluate the antitumor activity of MLM-CAR44.1 T-cells.
For more objectives please refer to the protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent before any study-related procedure.
2. Adults and children:
a) Adults 18 to 75 years old with AML or MM
b) Children 1 to 17 years old with AML, only in Phase IIa
3. Confirmed diagnosis of AML or MM as follows:
a) AML: Primary or secondary AML (any subtype except acute promyelocytic leukemia) according to World Health Organization (WHO) classification
b) MM with measurable disease as defined by the International Myeloma Working Group (IMWG).
4. Patients with relapse or refractory disease:
a) AML patients must be unlikely to benefit from cytotoxic chemotherapy as follows:
• Leukemia refractory to at least 2 induction attempts (use of a hypomethylating agent for at least 4 cycles can be considered a line of treatment).
• Leukemia in relapse within 1 year following complete response (CR) after at least 2 induction attempts (use of a hypomethylating agent for at least 4 cycles can be considered a first line of treatment).
• High-risk leukemia in adults according to 2017 European LeukemiaNet (ELN) in first relapse after a hypomethylating agent or a cycle containing cytarabine at a dose ≥ 1g/sqm a day (e.g. FLAG-IDA), except for FLT3-mutated AML.
• High-risk leukemia in children as defined by the Italian Association of Pediatric Hematology and Oncology (AIEOP).
b) Patients with MM must have a relapse or refractory disease after at least 4 different prior treatments in 3 treatment lines, or 4 treatments in 2 treatment lines in case of early relapsing patients (relapse in less than 1.5 years). Treatments include:
• Proteasome inhibitor
• High-dose alkylating agent if patient less than 70 years old
• Immunomodulatory drug (IMID)
• A monoclonal antibody (i.e. anti CD38 monoclonal antibody)
5. Positive CD44v6 expression on tumor cells by flow cytometry.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
7. Life expectancy of at least 12 weeks.
8. Adequate organ function:
a) Alanine aminotransferase (ALT) level within 2.5 times the institutional upper limit of normal (ULN).
b) aspartate aminotransferase (AST) level ≤ 2.5 x ULN.
c) Total bilirubin level ≤ 1.5 x ULN, or ≤ 2.5 x ULN in case of history of Gilbert’s disease.
d) Serum creatinine ≤ 2.0 mg/dL or a calculated or measured creatinine clearance ≥ 45mL/min.
e) Corrected Diffusing Capacity of Carbon Monoxide (DLCO) (via Dinakara Equation) or FEV1 of 66% without dyspnea on slight activity after hemoglobin correction.
f) Left ventricular ejection fraction ˃ 45%.
9. Recovery from toxicities of clinical consequence attributed to previous chemotherapy to CTCAE v5.0 Grade 1 (i.e., certain toxicities such as alopecia will not be considered in this category).
10. Ability to comply with study procedures, including hospitalization and protocol-specified acquisition of blood and/or bone marrow specimens.
11. Willing to be followed up long-term (15 years) as required by health authorities for cell and gene therapy products
12. Women of childbearing potential must have test negative for pregnancy at enrolment and during the study and agree to use an effective method of contraception. |
|
| E.4 | Principal exclusion criteria |
1. History of or candidate for allogeneic stem cell transplantation.
2. Cardiovascular, pulmonary, renal, and hepatic
functions that in the judgment of the investigator are insufficient to undergo investigational CAR T-cell therapy.
3. Any history of or suspected current autoimmune disorders (apart from vitiligo, resolved childhood atopic dermatitis, Graves’ disease clinically controlled).
4. History of rheumatologic disorders requiring specific treatment at any time in the patient’s medical history.
5. Second primary malignancy that requires active therapy. Adjuvant hormonal therapy is allowed.
6. Known or suspected central nervous system (CNS) leukemia.
7. Presence or history of myeloid sarcoma or any extramedullary mass.
8. Any medical or psychiatric condition that may limit compliance or increase safety risks, such as:
a) Active uncontrolled infection (including, but not limited to viral, bacterial, fungal, or mycobacterial infection).
b) Patients with known multiple antibiotic resistant infections in their clinical history.
c) Known human immunodeficiency virus infection, active or chronic hepatitis B or C infection.
d) Grade 3 or 4 bleeding.
e) Uncontrolled hypertension (systolic pressure > 180 mm Hg or diastolic pressure > 100 mm Hg).
f) Clinically significant arrhythmia, clinically significant baseline QTcF, or QTcF > 480 msec.
g) Unstable angina.
h) Myocardial infarction within 6 months prior to study drug administration.
i) Clinically significant heart disease (e.g. CHF NYHA III or IV, unstable coronary artery disease, myocardial infarction < 6 mo. prior to study entry).
j) Pregnancy or breast feeding.
k) Major surgery or trauma within 4 weeks before enrollment.
l) Dementia or altered mental status that would preclude sufficient understanding to provide informed consent.
Once all the above eligibility criteria are confirmed, a lymphocyte apheresis product of non-mobilized cells must be received and accepted by the manufacturing site. Note: the lymphocyte apheresis product will not be shipped or assessed for acceptance by the manufacturing site until documented confirmation of all other inclusion/exclusion criteria have been satisfied.
Prior to lymphocyte apheresis (week -9 to -7), the following criteria must be met:
1. Peripheral blast count ≤ 20,000/mm3 (AML).
2. No treatment with any other investigational agent in the previous 4 weeks.
3. No treatment with an immunostimulatory agent (IMIDs are allowed) or any cell therapy in the previous 30 days.
4. Negative to the following tests: HCV (Antibody, NAT), HIV 1-2 (p24, AB, Ag and NAT), total Ig Treponema Pallidum (if positive perform specific test), Australia HBsAg, total anti HB core Ab (if positive perform HBV DNA NAT), mycoplasma (PCR or IgM) and HTLV I-II.
Prior to lymphodepleting chemotherapy and MLM-CAR44.1 T-cell infusion (day -5 to day -3), the following criteria must be met:
1. Evidence of active disease at the beginning of lympho-depleting chemotherapy.
2. The following medications are excluded and should not be administered concomitantly or following lymphodepleting chemotherapy:
a) Monoclonal antibodies in the 8 weeks prior to MLM-CAR44.1 T-cell infusion are prohibited.
b) Salvage chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m2, anthracyclines, cyclophosphamide, proteasome inhibitors, IMIDs) must be stopped > 2 weeks prior to lymphodepleting chemotherapy
c) Granulocyte colony stimulating or granulocyte-macrophage colony stimulating factor in the 2 weeks prior to study CAR T-cell administration.
d) Immunosuppressant medications in the 2 weeks prior to CAR T-cell administration.
e) Cytosine arabinoside < 100 mg/m2/day must be stopped > 1 week prior to MLM-CAR44.1 T-cell infusion.
f) Therapeutic systemic doses of steroids must be stopped > 72 hours prior to product infusion. However, < 12 mg/m2/day hydrocortisone or equivalent are allowed as physiological replacement doses of steroids.
g) Hydroxyurea must be stopped > 72 hours prior to MLM-CAR44.1 T-cell infusion.
3. No cardiovascular, pulmonary, renal, and hepatic
functions that in the judgment of the investigator are insufficient to undergo investigational CAR T-cell therapy.
4. Female patients of childbearing potential must have a negative pregnancy test within 24 hours prior to starting lymphodepleting therapy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I:
1. MTD established through BOIN design and the following DLTs:
a. Grade 4 CRS
b. Grade 3 or higher CRS not responsive to therapy with steroids and or tocilizumab/siltuximab within 24 hours
c. Grade 3 or higher toxicity possibly related to treatment with MLM-CAR44.1 T-cells excluding hematological toxicities
d. Skin toxicities:
- NCI-CTC grade 3 or higher erythroderma (generalized exfoliative dermatitis)
- Stevens-Johnson syndrome
- Any other grade 3 or higher skin toxicity histologically confirmed as being related to CAR T-cell treatment
e. Grade 3 or higher neurotoxicity
2. Type, frequency and severity of adverse events and monitoring of systemic reactions (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
3. Absence of replication competent retrovirus (RCR) monitored by DNA PCR for the Galv gene.
Phase IIa:
Hematologic disease response:
- AML: CR, CRi and PR rate as per ELN criteria.
- MM: ORR: (sCR, CR, VGPR, and PR) as per IMWG criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I:
1. Within 30 days following CAR T-cell infusion
2. For 30 days following CAR T-cell infusion
3. 3, 6, 12 months after infusion and then yearly
Phase IIa:
- 2 months after MLM-CAR44.1 T-cell infusion
- 3 months after T-cell infusion |
|
| E.5.2 | Secondary end point(s) |
Phase I:
1. Hematologic disease response:
a. AML: complete response (CR), incomplete response (CRi) and partial response (PR) according to ELN criteria.
b. MM: overall response rate (ORR): stringent complete response (sCR), CR, very good partial response (VGPR) and partial response (PR) according to IMWG criteria.
2. Levels of circulating MLM-CAR44.1 T-cells by flow cytometry.
3. Suicide gene activation and elimination of transduced cells through administration of ganciclovir in case of cytokine release syndrome or other significant MLM-CAR44.1 T-cell related toxicities.
4. To set-up a validation process among the participating centers for the CD44v6 marking of tumor cells (AML and MM).
Phase IIa:
1. Hematologic disease response:
a. AML: CR, CRi and PR rate as per ELN criteria, 1 month and 6 months after MLM-CAR44.1 T-cell infusion. Morphologic leukemia-free state (MLFS).
b. MM: ORR (sCR, VGPR and PR) as per IMWG criteria.
2. Overall Survival (OS) at 2 years.
3. Disease-Free Survival (DFR) in AML patients.
4. Event Free Survival (EFS) in AML patients.
5. Progression Free Survival (PFS) in MM patients at 2 years.
6. Duration of Remission (DOR) in MM patients. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I:
1a. 1 and 2 months following MLM-CAR44.1 T-cell infusion
1b. 1 and 3 months following T-cell infusion
2. At day 7, 14, 21, 28, 60, 90, 180
3. For each dose level
4. During the study
Phase IIa:
1a. 1, 2 and 6 months after MLM-CAR44.1 T-cell infusion
1b. 1,2 and 6 months after T-cell infusion
2. From MLM-CAR44.1 T-cell infusion to death due to any cause
3. From achievement of response to relapse or death due to any cause during response
4. From the date of MLM-CAR44.1 T-cell infusion to the date of the earliest of the following: last follow-up, resistance, relapse or death due to any cause
5. From MLM-CAR44.1 T-cell infusion to progression/relapse or death due to any cause
6. From achievement of response to relapse or death due to any cause |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Antitumor activity of autologous CD44v6 CAR T-cells |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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