Study Assessing RLT Using [177Lu]Lu-PentixaTher for Relapsed/Refractory CXCR4+ Acute Leukemia.

Phase 2Active Not RecruitingNCT06356922

Nantes University Hospital21 enrolled

Overview

CXCR4 inhibition may represent a new therapeutic strategy in acute leukemia (AL) patients, not only by increasing chemosensitivity but also by preventing relapse of the disease by disruption of the interaction of residual leukemic cells with the bone marrow niche. Radiolabeled CXCR4 ligands have been developed for PET imaging (68Ga-PentixaFor; INN: Gallium (68Ga) boclatixafortide) and radioligand therapy (RLT) (\[177Lu\]Lu-PentixaTher/\[90Y\]Y-PentixaTher). \[177Lu\]Lu and \[90Y\]Y-PentixaTher have been tested in three multiple myeloma patients in named-patient use with a remarkable efficacy in 2 patients (Herrmann, 2016). Moreover, feasibility of CXCR4 PET imaging in AML was reported, providing a framework for future theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche (Herhaus, 2016). Here a Phase I/II study to determine maximal tolerated dose (MTD) of a RLT using \[177Lu\]Lu-PentixaTher in relapsed/refractory AL was designed. This will be a standard phase I/II 3+3 dose escalation study. Five dose levels will be tested, so 6 to 21 patients have to be included in the study.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Leukemia

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥ 18 years * AML/ALL (OMS) with \>5% of blasts in bone marrow (with or without extramedullary localisation) * CXCR4+ (ratio \>2/isotypic control) at the time of pre-inclusion * All previously treated AML/ALL patients who have experienced relapse or treatment failure with no alternative treatment * At least 15 days since previous treatment * Eastern Cooperative Oncology Group (ECOG) performance status \< 2 * eGFR ≥ 50 ml/min by MDRD or CKDEPI * ASAT or ALAT \> 5 upper normal value (except in case of documented presence of leukemia in the liver) * Serum bilirubin ≤ 30 µmol/l * Negative pregnancy test documented prior to enrolment (for females of childbearing potential) * Agree to use an effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile) * No active cardiac dysfunction (LVEF \> 45%) * DLCO \>40% * Written informed consent * Be willing and able to comply with scheduled visits and study procedures * Affiliation with French social security system or beneficiary from such system Exclusion Criteria: * Meningeal involvement * HIV positive * Active Hepatitis B or C * Active infection within 7 days of starting treatment * Previous or concurrent second malignancy except for adequately treated basal cell carcinoma of the skin, curatively treated in situ carcinoma of the cervix, curatively treated solid cancer, with no evidence of disease for at least 1 year * Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule * Participation at the same time in another study in which investigational drugs are used * Patient with contra-indications to Rhu-EPO, Rhu-GCSF, allopurinol, rasburicase, anti-histamines and corticosteroids * Absence of written informed consent * Pregnant or child breast feeding woman * Patient under guardianship or trusteeship * Patient under judicial protection

Outcomes

Primary Outcomes

Safety of RLT using one injection of [177Lu]Lu-PentixaTher

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Time frame: Between Week 4 and Week 6

Tolerance

Tolerance of the RLT will be evaluated by dosimetry studies, especially in terms of renal and hepatic doses delivered

Time frame: Between Week 4 and Week 6

Secondary Outcomes

Overall response rate

Response evaluation (CR, CRp and PR) after the infusion of \[177Lu\]Lu-PentixaTher

Time frame: Between Week 4 and Week 6

Complete response rate

Response evaluation (CR, CRp) after the infusion of \[177Lu\]Lu-PentixaTher

Time frame: Between Week 4 and Week 6

Overall survival

Time interval from the date from initial of study treatment (D0) until the date of last follow-up or death

Time frame: Month 12

Leukemia-free survival

Time interval from the date of documented complete response (CR, CRp) until the date of last follow-up, death or relapse

Time frame: Month 12

Minimal residual disease

CXCR4 ratio by flow cytometry after \[177Lu\]Lu-PentixaTher

Time frame: Month 12

Whole-body biodistribution

Serial whole body scintigraphies

Time frame: Between Week 4 and Week 6

Plasma uptake

The activity in each plasma sample will be determined by counting 0,2 ml of plasma in a calibrated gamma counter with an appropriate window setting. The maximal uptake (%) and area under the curve (AUC) of \[ 177Lu\]Lu-PentixaTher at the target lesion, organs and blood will be determined

Time frame: Between Week 4 and Week 6

Radiation dosimetry

Whole body quantitative scintigraphies

Time frame: Between Week 4 and Week 6

Renal safety

Renal safety will be assessed by measuring creatinine

Time frame: Month 12

Renal safety

Renal safety will be assessed by measuring urea

Time frame: Month 12

Renal safety

Renal safety will be assessed by measuring eGFR by MDRD or CKDEPI

Time frame: Month 12

Correlation between different cytokines and toxicity

FLT3 and IL6 serum level

Time frame: Month 12

Factors associated response

Responses will be evaluated 4/6 weeks after the infusion of \[177Lu\]Lu-PentixaTher (Day 0): Complete remission (CR) is defined by normalization of the blood and the bone marrow with \< or = 5% of blasts, neutrophil count \> 1.109 /l and platelet count \>100 Giga/l. CR with incomplete platelets recovery (CRp) is defined as for CR including platelet transfusion independence but with platelet count remaining below 100 Giga/l. Partial response (PR) is defined by blast clearance ≥50% in blood or bone marrow or bone marrow with \> 5% and \< 20 % of blasts

Time frame: Month 12

Exploratory outcome measure = Identification of biological biomarkers

Different cytokines including FLT3 and IL6 serum levels will be monitored by serial blood sampling at D1, D8, D15, D22 as well as during the monitoring visits at 1 month, and only FLT3 and IL6 at 3, 6, 9 and 12 months

Time frame: Month 12

Study Assessing RLT Using [177Lu]Lu-PentixaTher for Relapsed/Refractory CXCR4+ Acute Leukemia.

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes