Clinical trial NCT06132737: [90Y]Y-PTT Endoradiotherapy in CNS Lymphoma Patients
Official title: An Open-label Dose Escalation Study to Evaluate Safety, Tolerability, Biodistribution and Efficacy of [90Y]Y-PentixaTher for the Therapy of Recurrent or Refractory Primary or Isolated Secondary Central Nervous System Lymphoma.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: CNS Lymphoma
Lead sponsor: Pentixapharm AG
Sponsor class: INDUSTRY
First posted: 2023-11-15
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This will be an open-label, single-arm, national phase 1/2 therapeutic study to evaluate the safety, tolerability, and preliminary efficacy of \[90Y\]Y-PentixaTher (\[90Y\]Y-PTT) for the treatment of recurrent or refractory primary or isolated secondary central nervous system (CNS) lymphoma.

The study will be performed in three cohorts with different dose levels according to the best-of-5 dose escalation design. A safety review committee (SRC) will evaluate dose-limiting toxicities and decide about escalation and de-escalation.

Eligible patients will receive one cycle of \[90Y\]Y-PTT, which will be administered intravenously. There will be no comparator in this study.

Safety, biodistribution, dosimetry and efficacy will be evaluated during the core study phase (Visit 1 until Visit 5). Thereafter three follow-up (FU) visits will take place, at three-months intervals to evaluate the extent of disease.


Eligibility criteria: Inclusion Criteria:

Patients are eligible to be included in the study only if all of the following criteria apply and are maintained at Day -2 to Day 0 (before IMP infusion):

1. Signed informed consent, by the patient or an authorized legal guardian in case the patient is temporarily not competent due to his or her disease, obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study.
2. Patients of either gender aged \> 18 years.
3. Body weight \< 180 kg.
4. At least one measurable lymphoma manifestation in the CNS, either contrast-enhanced lesion in the brain parenchyma or measurable meningeal lesion.
5. Histologically, cytologically or radiologically confirmed relapsed/refractory primary central nervous system lymphoma (PCNSL) or relapsed/refractory secondary central nervous system lymphoma (SCNSL). Initial histologic confirmation at first diagnosis is mandatory. No peripheral lymphoma evidence is allowed.
6. Recurrent or refractory CNSL

   1. For recurrent disease, comprising new lesions or recurrent CNSL after a complete response (CR) at that site, there are no maximum number of recurrences.
   2. Refractory CNSL comprises patients with non-responding CNSL (no objective response rate (ORR), no progressive disease (PD)) to frontline therapy, or progressive disease after an initial, partial response (PR).
7. Stored stem cells with at least ≥ 2 x 106 CD34+ cells/kg of body weight.
8. If sexually active female patient of childbearing potential: patient agrees to take adequate contraceptive measures during study participation and agrees to continue use of this method for the duration of the study and for six months after the last dose.
9. Female patient without childbearing potential: documented history (e.g., tubal ligation or hysterectomy) or is post-menopausal.
10. For male patient whose partner is of child-bearing potential: patient is willing to ensure that he and his partner use effective contraception during the study and for six months after 90Y-PTT treatment.
11. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
12. Confirmed presence of CXCR4 on technically evaluable tumor lesions documented by a visually CXCR4-positive \[68Ga\]Ga-PentixaFor positron emission tomography (PET) scan within two months prior to enrolment in the study or during Screening.
13. Blood test results as follows:

    1. Absolute neutrophil count: \> 1.0 x 109/L
    2. Hemoglobin: ≥ 8 g/dL
    3. Platelets: ≥ 75 x 109/L
    4. Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP): ≤ 3 x ULN (upper limit of normal)
    5. Serum creatinine: ≤ 2 x ULN and Cockcroft Gault calculated glomerular filtration rate (GFR) ≥ 50 mL/min
    6. Bilirubin: ≤ 3 x ULN

Exclusion Criteria:

Patients are excluded from the study if any of the following criteria apply during screening or Day -2 to Day 0 (before IMP infusion):

1. Known or suspected hypersensitivity to study product(s) or related products.
2. Contraindication for contrast-enhanced magnetic resonance imaging (MRI) as set out in the relevant institutional guidelines (e.g., pacemaker, defibrillator, aneurysm clip, metal in the body, renal insufficiency, severe claustrophobia etc.) or contraindication for the use of gadolinium contrast for MRI.
3. Previous participation in this study. Participation is defined as signed informed consent.
4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice). A pregnancy test will be performed at the start of the study for all female patients of childbearing potential (i.e., not surgically sterile or two years postmenopausal).
5. Male of reproductive age who or whose partner(s) is not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice).
6. Participation in any clinical study of an approved or non-approved investigational medicinal product (IMP) within the last 30 days (or ≤ 5 terminal elimination half-lives of previous IMP, whichever is longer) before screening.
7. Any disorder (e.g., active infection, unstable angina pectoris, cardiac arrhythmia (excluding atrial fibrillation and atrial flutter, uncontrolled congestive heart failure), poorly controlled hypertension, poorly controlled diabetes mellitus \[HbA1c ≥ 9%\], etc.) or laboratory findings, except for conditions associated with CNS lymphoma, which in the investigator's opinion might jeopardize patient's safety or compliance with the protocol.
8. Presence of active infection, or history of serious infection six weeks prior to IMP administration. Patients with uncontrolled human immunodeficiency virus (HIV) infection as well as acute or chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are excluded (Note: Patients on antiretroviral therapy (ART) with controlled HIV infection (defined as sufficient ART compliance, non-measurable HIV and CD4+ T helper cells \> 200/Micro Liter) may be enrolled, if considered eligible for study treatment by the investigator.).
9. SCNSL with systemic involvement.
10. Chronic use (\> 21 days) of immunosuppressive drugs, e.g., steroids for systemic autoimmune disease, due to previous organ transplantation, or other clinically evident form of immunodeficiency. Patients receiving only acute treatment (less than 21 days) with corticosteroids can be included.
11. Any mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study, and/or evidence of an uncooperative attitude without designated legal representative.
12. Brain radiation therapy ≤ 180 days before IMP infusion.

Primary outcomes:
measure: Incidence, severity and relationship of (S)AEs (graded in severity according to NCI CTCAE version 5.0)
timeFrame: From screening until including the last follow-up visit. SAEs occuring after the end of the study should only be reported to Pentixapharm if the Investigator considers there is a causal relationship with the study drug.
Secondary outcomes:
measure: Maximal uptake (%) for tumor lesion
timeFrame: 1 ± 0.5 hours post infusion (p.i.).; 5 ± 1 hours p.i.; 22 ± 4 hours p.i.; 30 ± 4 hours p.i.
measure: Maximal uptake (%) in discernible organs
timeFrame: 1 ± 0.5 hours post infusion (p.i.); 5 ± 1 hours p.i.; 22 ± 4 hours p.i.; 30 ± 4 hours p.i.
measure: TAC in discernible thoracic and abdominal organs, target lesion and blood
timeFrame: Discernible thoracic /abdominal organs /target lesion: 1 ± 0.5 hours post infusion (p.i.).; 5 ± 1 hours p.i.; 22 ± 4 hours p.i.; 30 ± 4 hours p.i. For Blood: 5 ± 2 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 5 ± 1 hours, 22 ± 4 hours, 48 ± 6 hours p.i.
measure: AUC of 90Y-PTT in discernible thoracic and abdominal organs, target lesion and blood
timeFrame: Discernible thoracic /abdominal organs /target lesion: 1 ± 0.5 hours post infusion (p.i.).; 5 ± 1 hours p.i.; 22 ± 4 hours p.i.; 30 ± 4 hours p.i. For blood: 5 ± 2 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 5 ± 1 hours, 22 ± 4 hours, 48 ± 6 hours p.i.
measure: AUC of 90Y-PTT in urine
timeFrame: 0 - 5 hours (before 2nd PET scan); 5 - 22 hours (before 3rd PET scan); 22 - 48 hours
measure: Organ receiving the highest absorbed dose
timeFrame: 1 ± 0.5 hours post infusion (p.i).; 5 ± 1 hours p.i.; 22 ± 4 hours p.i.; 30 ± 4 hours p.i.
measure: Cumulative absorbed organ/lesion doses (Gy)
timeFrame: 1 ± 0.5 hours post infusion (p.i).; 5 ± 1 hours p.i.; 22 ± 4 hours p.i.; 30 ± 4 hours p.i.
measure: ORR at one month and three months
timeFrame: Month 1 (Visit 4) and Month 3 (Visit 5)
measure: PFS at one month and three months
timeFrame: Month 1 (Visit 4) and Month 3 (Visit 5) post infusion
measure: Rate of CR and PR at one month and three months
timeFrame: Month 1 (Visit 4) and Month 3 (Visit 5) post infusion
measure: PFS at 12 month (including a nine-month FU according to the local investigator's discretion)
timeFrame: 6 months post infusion (p.i.); 9 months p.i.; 12 months p.i.;
measure: OS at 12 month (including a nine-month FU according to the local investigator's discretion)
timeFrame: 6 months post infusion (p.i.); 9 months p.i.; 12 months p.i.;
Other outcomes:
measure: Incidence and severity of DLT
timeFrame: Up to 28 days post infusion
measure: Changes from baseline in vital signs
timeFrame: Baseline: -28 to -8 days before infusion; End of infusion; 5 ± 2 / 30 ± 5 minutes post infusion (p.i) ; 1 hour ± 10 minutes p.i.; 5 ± 1 / 22 ± 4 hours p.i. ; 22 to 48 hours p.i.; 2 / 14 days p.i.; 1/ 3 / 6 / 9 / 12 months p.i.
measure: Changes from baseline in laboratory parameters (hematology and biochemistry)
timeFrame: Hematology/Biochemistry: -28 to -8 days before infusion; Before infusion; 5 ± 1 hours post infusion (p.i.).; 2 days p.i.; 14 ± 2 days p.i; 1 / 3 months ± 5 days p.i.; 6 / 9 / 12 months ± 14 days p.i.;
measure: Changes from baseline in laboratory parameters (urinalysis)
timeFrame: Urinalysis: -28 to -8 days before infusion; 0 to 5 hours post infusion (p.i.) (before 2nd scan); 5 to 22 hours p.i.(before 3rd scan); 22 to 48 hours p.i.(before 4th scan); 2 days p.i.; 14 ± 2 days p.i; 1 / 3 months ± 5 days p.i.;
measure: Abnormal findings in physical examination
timeFrame: -28 to -8 days before infusion; Before infusion; 2 days post infusion (p.i.); 14 ± 2 days p.i; 1 / 3 months ± 5 days p.i.; 6 / 9 / 12 months ± 14 days p.i.;
measure: Findings12-lead ECG
timeFrame: -28 to -8 days before infusion; Before infusion; 5 ± 1 hours post infusion (p.i.); 2 days p.i.; 14 ± 2 days p.i; 1 / 3 months ± 5 days p.i.
Locations:
city: Munich
country: Germany
facility: University Hospital Rechts der Isar
state: Bavaria
city: Essen
country: Germany
facility: University Hospital Essen
Study officials:
affiliation: University Hospital, Essen
name: Bastian von Tresckow, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: