Phase I/II Study of CXCR4-Directed Theranostics Using [90Y]Y-PentixaTher and [68Ga]Ga-PentixaFor in Advanced Non-Hodgkin Lymphomas

The primary objective of the study is to define the maximum tolerated activity of **[90Y]Y-PentixaTher** when used in combination with high-dose chemotherapy, such as Melphalan or Treosulfan, followed by autologous stem cell transplantation (autoSCT) in patients with advanced **Non-Hodgkin lymphomas (NHL)**. This is crucial for determining the optimal therapeutic dose that maximizes efficacy while minimizing adverse effects, thereby improving patient outcomes in this population.

Secondary objectives include:

• Phase I: Assessment of the radiation dose received by the patient.
• Phase II: Evaluation of median progression-free survival (PFS), overall survival (OS), safety and tolerability, and hematopoietic recovery, as measured by complete blood counts (CBCs).

The clinical trial involves participants diagnosed with **Non-Hodgkin lymphomas (NHL)**, focusing on individuals with a histologically proven diagnosis of active measurable lymphoproliferative malignancies. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fit for high-dose chemotherapy and autologous stem-cell transplantation. Participants are required to have adequate hematopoietic, hepatic, renal, cardiac, and pulmonary function, excluding organ dysfunctions associated with the underlying disease. The trial includes individuals who are not currently suitable for allogeneic hematopoietic stem cell transplantation. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the inclusion of patients with a positive 68Ga-Pentixafor PET/CT imaging and the availability of CD34+ peripheral blood hematopoietic stem cells. Lifestyle considerations such as diet and physical activity are not specified, but women of childbearing potential must adhere to strict contraceptive measures. The trial population is selected based on specific medical and health criteria, ensuring participants are deemed fit for the study's high-dose chemotherapy regimen.

The clinical trial is designed to evaluate the efficacy and safety of **[90Y]Y-PentixaTher** in combination with high-dose chemotherapy for patients with advanced lymphoproliferative cancers, specifically **Non-Hodgkin lymphomas (NHL)**. This study is structured as a Phase I/II trial, incorporating a randomized, double-blind, and controlled methodology. The trial is expected to commence on September 2, 2024, and conclude by September 30, 2028. The primary objective in Phase I is to determine the maximum tolerated dose (MTD) of **[90Y]Y-PentixaTher**, while Phase II aims to assess the overall response rate (ORR) of the treatment regimen established in Phase I.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically proven diagnosis of active measurable lymphoproliferative malignancies, positive **68Ga-PentixaFor** PET/CT imaging, and adequate organ function. Following the screening, participants will be enrolled and receive the investigational treatment. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, including dosimetric analysis and assessment of hematopoietic recovery. The end-of-study visit will evaluate the long-term outcomes and any adverse events experienced by the participants.

The expected length of participant involvement in the trial is contingent upon the treatment phase and individual response, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. Conditions that may lead to early termination include severe organ dysfunctions not associated with the underlying disease or failure to adhere to the study protocol. Participants are required to use effective contraception during the trial and for a specified period after the last treatment visit to prevent pregnancy-related complications.

The clinical trial involves the use of **[68Ga]Ga-PentixaFor**, a radiopharmaceutical solution for injection, developed by PentixaPharm GmbH. This experimental medication is composed of the active substances **gallium (68Ga)** and **pentixafor**, both of which are of chemical origin. The pharmaceutical form is a solution for injection, administered via the intravenous route. The frequency and dosage of administration are determined based on the specific requirements of the trial protocol. The primary role of [68Ga]Ga-PentixaFor in this study is for diagnostic purposes, as it is classified under the ATC code V09IX, which pertains to other diagnostic radiopharmaceuticals for tumor detection. Participant compliance with the administration schedule is monitored throughout the trial to ensure adherence to the protocol.

Additionally, the trial utilizes **[90Y]Y-PentixaTher**, another solution for injection provided by PentixaPharm GmbH. This investigational product contains the active substances **pentixather** and **yttrium-90**, with pentixather being of protein origin and yttrium-90 of chemical origin. The administration of [90Y]Y-PentixaTher is also conducted intravenously. The medication is categorized under the ATC code V10XX, indicating its use as a therapeutic radiopharmaceutical. The trial aims to establish the maximum tolerated activity of [90Y]Y-PentixaTher in combination with high-dose chemotherapy, followed by autologous stem cell transplantation. The dosing schedule and participant compliance are rigorously monitored to ensure the integrity of the trial data.

In this study, standard-of-care therapies, such as high-dose chemotherapy agents like Melphalan and Treosulfan, are used in conjunction with the investigational treatments. These non-experimental treatments are administered according to established medical guidelines and are integral to the trial's therapeutic strategy. The combination of these therapies aims to evaluate the overall response rate in patients with advanced lymphoproliferative cancers, as outlined in the trial's objectives.

The clinical trial aims to assess the efficacy of a treatment regimen for advanced lymphoproliferative cancers using radiopeptide-based imaging and therapy. The primary efficacy endpoints for this trial are defined separately for Phase I and Phase II. In Phase I, the primary endpoint is the determination of the maximum tolerated dose (MTD) of **[90Y]Y-PentixaTher** in combination with high-dose chemotherapy. In Phase II, the primary endpoint is the overall response rate (ORR) of the treatment regimen established in Phase I.

Secondary endpoints include dosimetric analysis to assess the radiation dose received by patients in Phase I, and in Phase II, the median progression-free survival (PFS), overall survival (OS), and hematopoietic recovery, which will be measured by the time course of complete blood counts (CBCs). Safety endpoints will also be evaluated, focusing on the frequency and severity of adverse events.