Phase I/II, open-label, multi-center study to evaluate the safety and efficacy of glyco-humanized polyclonal antibody directed against tumoral T cells, in patients with relapsed/refractory peripheral T cells lymphoma (PTCL).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Xenothera

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

9 Jul 2024 → ongoing

Decision date (initial)

2024-04-29

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic, Dose response, Others

Dose Escalation (Part 1):
- To assess safety and tolerability at increasing dose levels of LIS1 as single agent
- To identify the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of LIS1
Dose Expansion (Part 2):
- To assess anti-tumors efficacy of LIS1 in selected relapsed or refractory PTCL

Secondary objectives 7

1. Dose Escalation (Part 1) - To characterize the pharmacokinetics (PK) of LIS1
2. Dose Escalation (Part 1) - To assess the preliminary anti-tumor efficacy of LIS1
3. Dose Escalation (Part 1) - To assess host immunogenicity to LIS1
4. Dose Expansion (Part 2) - To further assess anti-tumor efficacy parameters of LIS1 in selected relapsed or refractory PTCL
5. Dose Expansion (Part 2) - To assess safety and tolerability of LIS1 in selected relapsed or refractory PTCL types
6. Dose Expansion (Part 2) - To assess host immunogenicity to LIS1
7. Dose Expansion (Part 2) - To further characterize the PK of LIS1

Conditions and MedDRA coding

Peripheral T cells lymphoma (PTCL)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Provide signed, written informed consent
2. Is male or female, age ≥18 years old (at the time consent is obtained)
3. For Part 1: Has a histological diagnosis of the following relapsed or refractory PTCL based on WHO 2022 classification of lymphoid neoplasms • Intestinal T-cell and NK cell lymphoid proliferations and lymphomas (without NK cell neoplasms) • Hepatosplenic T-cell lymphoma • Anaplastic large cell lymphoma • Nodal TFH cell lymphoma • Other peripheral t-cell lymphomas. For Part 2: The type of PTCL will be defined based on SC review after completion of Part 1 and will be documented in the protocol amendment
4. Had previously received 1 or more appropriate systemic therapies, including an alkylating agent and/or anthracycline, for treatment of the current disease (radiation therapy alone would not be acceptable as previous therapy). Participants with ALCL must have received prior brentuximab vedotin or be unable to receive it due to allergy or intolerance.
5. Experienced disease progression during or after completion of most recent therapy or refractory disease
6. Has a measurable lesion by imaging: the longest diameter should be ≥1.5 cm for nodal lesions and >1 cm for extra-nodal lesions.
7. Experienced a toxicity of prior therapy: Participants must have recovered to less than Grade 1 or to baseline from toxicity of prior chemotherapy or biologic therapy and must not have had major surgery, chemotherapy, radiation, or biologic therapy within 2 weeks prior to beginning treatment. Note: Exceptions to this include events not considered to place the participant at unacceptable risk of participation in the opinion of the Investigator (e.g., alopecia).
8. Has either unstained tissues (block or unstained slides) or stained slides and pathology report available for central review. If stained slides or unstained tissue are not available or insufficient, a fresh tumor tissue sample is mandatory for central pathology. Central pathology confirmation is not required prior to enrollment.
9. Is able to provide a bone marrow aspirate and/or a biopsy no older than 3 months at screening and agrees to undergo post-treatment bone marrow aspirate or biopsy when required to confirm response.
10. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
11. Has life expectancy of >3 months
12. Has an adequate hematological and organ function at screening, including: • Hemoglobin ≥8.0 g/dL (prior transfusion is acceptable) • Absolute neutrophil count (ANC) ≥1000 cells/mm3 (without growth factor support within 7 days of ANC measurement) • Platelet count ≥50,000 cells/mm3 (without growth factor support or transfusion within 7 days of platelets measurement) • Creatinine clearance ≥30 mL/min • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 × the upper limit of normal (ULN) • Serum total bilirubin <2 × ULN OR <3 × ULN (for participants with Gilbert’s Syndrome)
13. Participants must be able to understand and sign an informed consent form.
14. All participants must use adequate contraception during participation in this study and for 6 months following completing therapy.

Exclusion criteria 26

1. Is diagnosed with a bulky disease (≥10 cm)
2. Has a known infection with human immunodeficiency virus (HIV) or serologic status reflecting active hepatitis B or C infection as follows: • Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Participants with presence of HBcAb, but absence of HBsAg, are eligible only if hepatitis B virus (HBV) DNA is undetectable by an assay with sensitivity <20 IU/mL. If so, participants may either undergo regularly scheduled monitoring of HBV DNA or less frequent monitoring of HBV DNA while on prophylactic antiviral medication as defined by regional standard of care. • Presence of hepatitis C virus (HCV) antibody. Participants with presence of HCV antibody are eligible only if HCV RNA is undetectable.
3. Has a known active tuberculosis infection.
4. Has an active fungal, bacterial, and/or viral infection requiring systemic therapy
5. Had a vaccination with a live vaccine within 35 days prior to the first dose of LIS1
6. If woman, is pregnant or nursing a child.
7. Has an active autoimmune disease or history of autoimmune disease that may relapse except for type I diabetes under control, hypothyroidism managed with hormone replacement therapy, controlled celiac disease, and skin disease (vitiligo, psoriasis, etc.) not requiring systemic treatment.
8. Has a known history of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis, acute lung disease, or dyspnea at rest or pulse oxymetrie < 92% at room air.
9. Has a clinically significant cardiovascular disease including the following: • Myocardial infarction or unstable angina within 3 months before screening • Congestive heart failure (New York Heart Association functional classification III-IV) • History of clinically significant arrythmias • QTcF > 470 msec • History of Mobitz II second degree or third-degree heart block without a permanent pacemaker in place • Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure >170 mm Hg and diastolic blood pressure >105 mmHg at screening.
10. Has a cognitive impairment, active substance abuse, or psychiatric illness or social situations that, in the view of the Investigator, would preclude safe treatment or the ability to give informed consent and limit compliance with study requirements.
11. Has a known history of drug-induced liver injury, alcoholic liver disease, non- alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver or portal hypertension.
12. Has known history or presence of central nervous system involvement by leukemia or lymphoma.
13. Has a hemophilia or von Willebrand’s disease.
14. Has any psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
15. Has a concurrent condition that, in the Investigator’s opinion, would jeopardize compliance with the protocol.
16. Are unable or unwilling to comply with study and/or follow-up procedures outlined in the protocol.
17. For France, participants under legal protection (safeguard, guardianship, curatorship).
18. Is currently participating in another therapeutic clinical study.
19. Has Mature T-cell and NK-cell leukemias (WHO 2022 criteria)
20. Has T-lymphoblastic leukemia/lymphoma (WHO 2022 criteria)
21. Has tumor-like lesions with T-cell predominance (WHO 2022 criteria)
22. Has Primary cutaneous T-cell lymphomas (WHO 2022 criteria)
23. Has any other active cancers, or history of treatment for invasive cancer ≤3 years. Note: Participants with stage I cancer who have received definitive local treatment at least 3 years previously and are considered unlikely to recur are eligible. All participants with previously treated in situ carcinoma (i.e., non-invasive) are eligible.
24. Received any of the following treatments prior to the first dose of study medication: • Systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks (or 5 half-lives, whichever is shorter) before Cycle 1 Day 1. Participants that received local radiation therapy are eligible. • Therapeutic anti-cancer antibodies <4 weeks • Any investigational drug in the last 4 weeks prior • Any major surgery or immunotherapy within 28 days • Toxin immunoconjugates <4 weeks • Nitrosoureas <6 weeks • Allogeneic hematologic stem cell transplant within 3 months • Adaptive cellular therapy such as autologous or donor natural killer cell or T lymphocyte infusions within 90 days • Systemic corticosteroids (prednisone or equivalent >10 mg daily) within 2 weeks prior to the start of therapy, or 12 weeks if given to treat graft versus host disease (GVHD), except for physiological replacement doses of cortisone acetate or equivalent • Systemic treatment for GVHD (including but not limited to oral or parenteral corticosteroids, ibrutinib, and extracorporeal phototherapy) within the last 12 weeks
25. Is experiencing a toxicity (or AE) from prior anti-cancer treatment that has not resolved to Grade ≤1 or baseline.
26. Has a known hypersensitivity to polyclonal antibody.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Dose Escalation (Part 1) - Incidence of dose limiting toxicities (DLTs) in the first cycle; a cycle is 28 days in duration.
2. Dose Escalation (Part 1) - Incidence, intensity, and seriousness of treatment emergent adverse events (TEAEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5 except for tumor lysis syndrome which will be graded according to widely accepted specialized criteria provided in Appendix XI of the Protocol and cytokine release syndrome based on criteria in Appendix X of the Protocol..
3. Dose Escalation (Part 1) - Incidence and magnitude of clinically significant changes in clinical laboratory parameters.
4. Dose Escalation (Part 1) - Incidence and severity of clinically significant findings in vital signs, electrocardiogram (ECG), and other physical examination.
5. Dose Expansion (Part 2) - ORR defined as the proportion of participants with CR or PR assessed by Investigators according to Lugano criteria with the LYRIC modification for immunomodulatory drug within 3 months after LIS1 initiation

Secondary endpoints 18

1. Dose Escalation (Part 1) - LIS1 concentrations in serum and PK parameters including maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve (AUC) from 0 to 24 hours (AUC24h), AUC0-14 days, AUC15-28 days, AUC0-28 days half-life (T½), clearance (CL), volume of distribution (Vd), and minimum concentration (Cmin)
2. Dose Escalation (Part 1) - Objective response rate (ORR): defined as the proportion of participants with complete response (CR) or partial response (PR) assessed by the Investigators according to Lugano criteria with the LYRIC modification for immunomodulatory drug.
3. Dose Escalation (Part 1) - Duration of response: defined as the time interval between the first confirmed objective response (CR or PR per Lugano criteria) and the first occurrence of objective tumor progression (progressive disease [PD] per Lugano criteria) or death from any cause.
4. Dose Escalation (Part 1) - Time to response (TTR): defined as the time from the date of LIS1 initiation to the date of the first confirmed objective response (CR or PR per Lugano criteria).
5. Dose Escalation (Part 1) - Progression-free survival (PFS): defined as the time from the date of LIS1 initiation to the date of first documented progression (Lugano criteria) or death.
6. Dose Escalation (Part 1) - Overall survival (OS): defined as the time interval between the date of LIS1 initiation and the date of death due to any cause.
7. Dose Escalation (Part 1) - Number and percentage of participants who develop detectable anti-drug antibodies (ADA).
8. Dose Expansion (Part 2) - Proportion of each best overall response category (CR, PR, SD, and PD).
9. Dose Expansion (Part 2) - Duration of response.
10. Dose Expansion (Part 2) - TTR, PFS, and OS.
11. Dose Expansion (Part 2) - Incidence, intensity, and seriousness of TEAEs experienced according to the NCI CTCAE v5.
12. Dose Expansion (Part 2) - Incidence and magnitude of clinically significant changes in clinical laboratory parameters, suggestive of possible trends, but not necessarily establishing clinical abnormality.
13. Dose Expansion (Part 2) - Incidence and severity of clinically significant findings in vital signs, ECG, and other physical examination.
14. Dose Expansion (Part 2) - Frequency of dose interruptions and dose reductions.
15. Dose Expansion (Part 2) - Number and percentage of participants who develop detectable ADA.
16. Dose Expansion (Part 2) - LIS1 concentrations in serum and PK parameters including Cmax, Tmax, AUC24h, AUC0-14 days, AUC15-28 days, AUC0-28 days T½, CL, Vd, and Cmin.
17. Dose Escalation (Part 1) - Proportion of patients “bridged to transplantation”
18. Dose Expansion (Part 2) - Proportion of patients “bridged to transplantation”

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Xenothera

Sponsor organisation

Xenothera

Address

21 Rue La Noue Bras De Fer

City

Nantes

Postcode

44200

Country

France

Scientific contact point

Organisation

Xenothera

Contact name

Medical Director

Public contact point

Organisation

Xenothera

Contact name

Medical Director

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications