FIH XON7 in Advanced/Metastatic Solid Tumors

Phase 2RecruitingNCT06154291

Xenothera SAS255 enrolled

Overview

This is a two-stage trial consisting of a Part I, dose escalation and dose-finding component to establish the Maximal Tolerated Dose (MTD), if any, and Recommended Part 2 Dose (RP2D) of XON7, followed by a Part II component to investigate anti-tumors efficacy in selected solid tumor types and to further evaluate safety and tolerability of XON7 at RP2D.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

255

Conditions

Advanced Solid Tumor Metastatic Cancer

Interventions

XON7DRUG

The trial intervention (XON7) is a glyco-humanized polyclonal antibody drug which is formulated for intravenous (IV) administration

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Provide signed, written informed consent. 2. Male and female participant, age ≥ 18 years old (at the time consent is obtained) 3. Solid tumors indications: * Participant in phase I, must have a histologically or cytologically confirmed advanced or metastatic solid tumors for which no effective standard therapy is available. All tumor types except glioblastoma, could be included. * Participant in phase II, must have histologically or cytologically confirmed advanced or metastatic solid tumors of the following: NSCLC, gastro-esophageal adenocarcinoma, CRC, pancreatic cancer, Sarcoma, TNBC, or ovarian cancer. 4. Line of treatment: Participant must have solid tumors progressing after ≤ 4 lines of standard appropriate anticancer therapies for the specific tumor type, or for which the patient is ineligible. Participants whose cancers harbor molecular alterations for which targeted therapy is standard of care should have received health authority-approved appropriate targeted therapy for their tumor types before enrollment. 5. Measurable disease per RECIST version 1.1 - v5 6. (ECOG) performance status (PS) 0-1 7. Life expectancy of at least 12 weeks. 8. Adequate organ function 9. QT duration corrected for heart rate by Fridericia's formula (QTcF) \<450 msec or QTcF \<480 msec for participants with bundle branch block. 10. In France, a participant will be eligible for inclusion in this trial only if either affiliated to or a beneficiary of a social security category. 11. Female participant who are not of child-bearing potential, and female participants of child-bearing potential who have a negative serum pregnancy test within 7 days prior to initial trial treatment. Female participants of child-bearing potential, and all male partners must consent to use a medically acceptable method of contraception throughout the trial period and for at least 60 days after the last dose of XON7. A barrier method of contraception must be included. 12. Male participant willing to use adequate contraceptive measures throughout the trial period and for at least 60 days after the last dose of trial intervention. 13. For phase II, participant in pharmacodynamics cohort must provide biopsy of a tumor lesion not previously irradiated during the screening period and must agree to provide at least one additional on-treatment biopsy between day 36 and 42 after trial intervention administration. 14. For phase II, participant in pharmacodynamics cohort must have accessible tumor tissue available for fresh biopsy except for ovarian cancer and sarcoma. Exclusion Criteria: 1. A participant who has received more than 4 prior lines of therapy for advanced or metastatic disease. 2. A participant who has had a prior anti-cancer mAb within 3 weeks prior to trial Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier prior to trial Day 1. 3. A participant who has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to trial Day 1 or who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent (Except alopecia, hearing loss, grade 2 neuropathy or endocrinopathy managed with replacement therapy). 4. A participant with ≥Grade 3 toxicity related to prior immunotherapy leading to treatment discontinuation. 5. A participant whose toxicity related to prior treatment has not resolved to Grade 1 (except alopecia, hearing loss, grade 2 neuropathy or endocrinopathy managed with replacement therapy). 6. A participant who has received major surgery 2 weeks before the first dose of trial treatment or has not recovered adequately from the toxicity and/or complications from any surgery (major or minor) before initiating trial treatment. 7. Concomitant use of another experimental drug, or wash-out period of at least 5 half-lives for a previous experimental drug not completed before start of trial intervention 8. Participant treated with drugs known to prolong the QT interval 9. Participant with carcinomatous meningitis. 10. Central nervous system (CNS) metastases, with the exception of individuals who have been previously treated CNS metastases, are asymptomatic, and have had no requirement for steroids for 3 weeks prior to first dose of trial drug. 11. Malignancies other than disease under trial within 3 years prior to first dose of trial intervention. 12. History of autoimmune disease 13. Active or uncontrolled infections requiring systemic treatment (known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen or hepatitis C). 14. Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the trial such as history or evidence of cardiovascular risk including any of the following: * Recent (within the past 6 months) history of serious uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second degree (Type II) or third-degree atrioventricular block. * Documented cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within the past 6 months before enrollment. * Documented congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association functional classification system (NYHA, 1994). 15. Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation. 16. Current active liver or biliary disease (Except for Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per investigator assessment). 17. Concurrent medical condition requiring the use of systemic immunosuppressive medications within 28 days before the first dose of trial treatment. 18. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction. 19. Current or history of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing pneumonia. Note: post-radiation changes in the lung related to prior radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring treatment may be permitted if agreed by the investigator and Medical Monitor. 20. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. 21. Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions. 22. Participant who has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony- stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor \[GM- CSF\], recombinant erythropoietin) within 2 weeks before the first dose of trial intervention. 23. Known, current drug or alcohol abuse. 24. Female participant who is pregnant or lactating. 25. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol. 26. Inability or unwillingness to comply with trial and/or follow-up procedures outlined in the protocol. 27. For France, patients under legal protection (safeguard, guardianship, curatorship)

Locations (5)

Institut Jules Bordet

Anderlecht, Belgium

RECRUITING

Institut Bergonié

Bordeaux, France

RECRUITING

Centre Léon Bérard

Lyon, France

RECRUITING

Outcomes

Primary Outcomes

Dose Escalation part: Dose Limiting Toxicities (DLTs)

Investigator defined DLT during first treatment cycle

Time frame: At the end of Cycle 1 (28 days)

Dose Escalation part: treatment emergent adverse events (TEAEs)

An overall summary of AE occurrences with onset during the first treatment cycle will be presented; this will include the following AE attributes: * Preferred term, * Maximum CTCAE grade, * Outcome, * Time to first occurrence \[days\].

Time frame: At the end of Cycle 1 (28 days)

Dose Escalation part: clinically significant changes in Leucocytes count

Incidence and magnitude of clinically significant changes in Leucocytes Count (G/L)

Time frame: At the end of Cycle 1 (28 days)

Dose Escalation part: clinically significant changes in Red Blood Cells Count

Incidence and magnitude of clinically significant changes in Red Blood Cells Count (T/L)

Time frame: At the end of Cycle 1 (28 days)

Dose Escalation part: clinically significant changes in Hemoglobin

Incidence and magnitude of clinically significant changes in Hemoglobin (g/dL).

Time frame: At the end of Cycle 1 (28 days)

Dose Escalation part: clinically significant changes in Hematocrit

Incidence and magnitude of clinically significant changes in Hematocrit (%).

Time frame: At the end of Cycle 1 (28 days)

Dose Escalation part: clinically significant changes in Absolute Neutrophil Count

Incidence and magnitude of clinically significant changes in Absolute Neutrophil Count (G/L).

Central Contacts

Françoise SHNEIKER, MD

CONTACT

+33652720301 francoise.shneiker@xenothera.com

Alain BALEYDIER

CONTACT

+33672800375 alain.baleydier@xenothera.com

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Pharmacokinetics (PK) of XON7 (Part 1): Cmax

XON7 peak plasma concentration (Cmax) in plasma

Time frame: Cycle 1-Day 1 Predose and Postdose: 5 minutes; 1; 2; 4; 8; 24; 72 or 96; 144 hours after the end of infusion. Cycle 1 Day 15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 7 Day 1: Predose and 5 minutes after the end of infusion

Pharmacokinetics (PK) of XON7 (Part 2): Cmax

XON7 peak plasma concentration (Cmax) in plasma

Time frame: Cycle 1-Day 1; Cycle 2-Day 1; Cycle 3-Day 1; Cycle 6-Day 1; Cycle 9-Day1 and Cycle 12-Day 1: Predose and 5 minutes after the end of infusion

Pharmacokinetics (PK) of XON7 (Part 1): Tmax

Time to peak drug concentration in plasma (Tmax)

Pharmacokinetics (PK) of XON7 (Part 2): Tmax

Time to peak drug concentration in plasma (Tmax)

Time frame: Cycle 1-Day 1; Cycle 2-Day 1; Cycle 3-Day 1; Cycle 6-Day 1; Cycle 9-Day1 and Cycle 12-Day 1: Predose and 5 minutes after the end of infusion

Pharmacokinetics (PK) of XON7 (Part 1): AUC

Area under the plasma concentration versus time curve (AUC). AUC24hours; AUC0-14days and AUC15-28days will be assessed

Pharmacokinetics (PK) of XON7 (Part 2): AUC

Area under the plasma concentration versus time curve (AUC). AUC24hours; AUC0-14days and AUC15-28days will be assessed

Time frame: Cycle 1-Day 1; Cycle 2-Day 1; Cycle 3-Day 1; Cycle 6-Day 1; Cycle 9-Day1 and Cycle 12-Day 1: Predose and 5 minutes after the end of infusion

Pharmacokinetics (PK) of XON7 (Part 1): Ctrough

Trough concentration (Ctrough) is the concentration reached by XON7 immediately before the next dose is administered

Pharmacokinetics (PK) of XON7 (Part 2): Ctrough

Trough concentration (Ctrough) is the concentration reached by XON7 immediately before the next dose is administered

Time frame: Cycle 1-Day 1; Cycle 2-Day 1; Cycle 3-Day 1; Cycle 6-Day 1; Cycle 9-Day1 and Cycle 12-Day 1: Predose and 5 minutes after the end of infusion

Pharmacokinetics (PK) of XON7 (Part 1): Cmin

Cmin for the minimum blood plasma concentration reached by XON7 during the time interval between administration of two doses

Pharmacokinetics (PK) of XON7 (Part 2): Cmin

Cmin for the minimum blood plasma concentration reached by XON7 during the time interval between administration of two doses

Time frame: Cycle 1-Day 1; Cycle 2-Day 1; Cycle 3-Day 1; Cycle 6-Day 1; Cycle 9-Day1 and Cycle 12-Day 1: Predose and 5 minutes after the end of infusion

Pharmacokinetics (PK) of XON7 (Part 1): T1/2

Half-life (T1/2) refers to the time required for plasma concentration of XON7 to decrease by 50%

Pharmacokinetics (PK) of XON7 (Part 2): T1/2

Half-life (T1/2) refers to the time required for plasma concentration of XON7 to decrease by 50%

Time frame: Cycle 1-Day 1; Cycle 2-Day 1; Cycle 3-Day 1; Cycle 6-Day 1; Cycle 9-Day1 and Cycle 12-Day 1: Predose and 5 minutes after the end of infusion

Pharmacokinetics (PK) of XON7 (Part 1): CL

Clearance (CL) is the volume of blood or plasma cleared of XON7 from the body per unit of time

Pharmacokinetics (PK) of XON7 (Part 2): CL

Clearance (CL) is the volume of blood or plasma cleared of XON7 from the body per unit of time

Time frame: Cycle 1-Day 1; Cycle 2-Day 1; Cycle 3-Day 1; Cycle 6-Day 1; Cycle 9-Day1 and Cycle 12-Day 1: Predose and 5 minutes after the end of infusion

Pharmacokinetics (PK) of XON7 (Part 1): Vd

Volume of distribution (Vd) is defined as the total amount of XON7 in the body divided by its concentration in plasma

Pharmacokinetics (PK) of XON7 (Part 2): Vd

Volume of distribution (Vd) is defined as the total amount of XON7 in the body divided by its concentration in plasma

Time frame: Cycle 1-Day 1; Cycle 2-Day 1; Cycle 3-Day 1; Cycle 6-Day 1; Cycle 9-Day1 and Cycle 12-Day 1: Predose and 5 minutes after the end of infusion

Host immunogenicity to XON7 (Part 1 and part 2)

Number of participants who develop detectable anti-drug antibodies

Time frame: Cycle 1-Day 1; Cycle 1-Day4; Cycle 1-Day7; Cycle 1-Day15; Cycle 2 and additional cycles-Day1; 30 and 60 days after the last dose of XON7

Host immunogenicity to XON7 (Part 1 and part 2)

Percentage of participants who develop detectable anti-drug antibodies

Time frame: Cycle 1-Day 1; Cycle 1-Day4; Cycle 1-Day7; Cycle 1-Day15; Cycle 2 and additional cycles-Day1; 30 and 60 days after the last dose of XON7

Further assess anti-tumor efficacy (Part 1): ORR

Objective response rate (ORR): defined as the proportion of participants with a confirmed complete response \[CR\] or confirmed partial response \[PR\] assessed by investigators according to RECIST v1.1. within 3 months after XON7 initiation

Time frame: Tumor imaging (computed tomography [CT]) will be performed within 28 days prior to enrollment, and while on study approximately every 8 weeks during the treatment period. During the survival follow-up, results of CT only performed in current practice

Further assess anti-tumor efficacy (Part 2): CBR

Clinical Benefit Rate (CBR) defined as the proportion of participants who achieve CR, PR, and durable SD \[SD≥24 weeks\] assessed by investigators according to the RECIST criteria v 1.1.

Further assess anti-tumor efficacy (Part 1 and part 2): DCR

Disease control rate (DCR): defined as the proportion of participants who achieve confirmed complete response \[CR\], confirmed partial response \[PR\] or stable disease \[SD\] assessed by investigators according to the RECIST criteria version 1.1.

Further assess anti-tumor efficacy (Part 1 and part 2): DoR

Duration of response (DoR): defined as the time interval between the first confirmed objective response (CR or PR per RECIST 1.1 by investigators) and the first occurrence of objective tumor progression (Progressive disease (PD) per RECIST 1.1 by investigators) or death from any cause.

Further assess anti-tumor efficacy (Part 2): TTR

Time to response (TTR): defined as the time from the date of XON7 initiation to first confirmed objective response (CR or PR per RECIST 1.1 by investigators)..

Further assess anti-tumor efficacy (Part 1 and part 2): PFS

Progression-free survival (PFS): defined as the time from the date of XON7 initiation to the date of first documented progression (RECIST 1.1 by investigators) or death.

Further assess anti-tumor efficacy (Part 1 and part 2): OS

Overall survival (OS): defined as the time interval between the date of XON7 initiation and the date of death due to any cause.

Expansion part: treatment emergent adverse events (TEAEs)

Time frame: Participants will be assessed for AEs and SAEs beginning immediately after the first dose of investigational drug and continuing through to follow-up which is 60 ± 5 days of last dose of investigational drug.

Dose Escalation part: clinically significant findings in blood pressure (BP)

Incidence and severity of clinically significant findings in blood pressure: Significant blood pressure increase will be defined as BP \>150/100 mmHg in a subject without a history of hypertension or increased \>20 mmHg (diastolic) from baseline measurement in a subject with a previous history of hypertension.

Time frame: Before and immediately after the first dose of investigational drug and continuing through to follow-up which is 60 ± 5 days of last dose of investigational drug

Dose Escalation part: clinically significant findings in electrocardiogram (ECGs)

Incidence of clinically significant findings in Electrocardiogram (ECG): Significant QTc prolongation will be defined as an interval ≥500 msec or an interval which increases by ≥60 msec over baseline

Time frame: Before and immediately after the first dose of investigational drug and continuing through to follow-up which is 60 ± 5 days of last dose of investigational drug

Expansion part: clinically significant changes in Leucocytes count

Incidence and magnitude of clinically significant changes in Leucocytes Count (G/L)

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Red Blood Cells Count

Incidence and magnitude of clinically significant changes in Red Blood Cells Count (T/L)

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Hemoglobin

Incidence and magnitude of clinically significant changes in Hemoglobin (g/dL).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Hematocrit

Incidence and magnitude of clinically significant changes in Hematocrit (%).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Absolute Neutrophil Count

Incidence and magnitude of clinically significant changes in Absolute Neutrophil Count (G/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Absolute Eosinophil Count

Incidence and magnitude of clinically significant changes in Absolute Eosinophil Count (G/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Absolute Basophil Count

Incidence and magnitude of clinically significant changes in Absolute Basophil Count (G/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Absolute Lymphocytes Count

Incidence and magnitude of clinically significant changes in Absolute Lymphocytes Count (G/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Absolute Monocytes Count

Incidence and magnitude of clinically significant changes in Absolute Monocytes Count (G/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Platelet Count

Incidence and magnitude of clinically significant changes in Platelet Count (G/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Albumin

Incidence and magnitude of clinically significant changes in Albumin (g/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Bicarbonate

Incidence and magnitude of clinically significant changes in Bicarbonate (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Total Bilirubin

Incidence and magnitude of clinically significant changes in Total Bilirubin (µmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Calcium

Incidence and magnitude of clinically significant changes in Calcium (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Urea

Incidence and magnitude of clinically significant changes in Urea (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Chloride

Incidence and magnitude of clinically significant changes in Chloride (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Creatinine

Incidence and magnitude of clinically significant changes in Creatinine (µmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Creatinine Clearance

Incidence and magnitude of clinically significant changes in Creatinine Clearance (mL/min).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Glucose

Incidence and magnitude of clinically significant changes in Glucose (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Magnesium

Incidence and magnitude of clinically significant changes in Magnesium (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Phosphate

Incidence and magnitude of clinically significant changes in Phosphate (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Potassium

Incidence and magnitude of clinically significant changes in Potassium (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Sodium

Incidence and magnitude of clinically significant changes in Sodium (mmol/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Total Protein

Incidence and magnitude of clinically significant changes in Total Protein (g/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Alanine aminotransferase (ALT)

Incidence and magnitude of clinically significant changes in Alanine aminotransferase (ALT) (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Aspartate aminotransferase (AST)

Incidence and magnitude of clinically significant changes in Aspartate aminotransferase (AST) (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Gamma-glutamyl transférase (GGT)

Incidence and magnitude of clinically significant changes in Gamma-glutamyl transférase (GGT) (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Alkaline Phosphatase (ALP)

Incidence and magnitude of clinically significant changes in Alkaline Phosphatase (ALP) (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Lactate dehydrogenase (LDH)

Incidence and magnitude of clinically significant changes in Lactate dehydrogenase (LDH) (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Amylase

Incidence and magnitude of clinically significant changes in Amylase (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Lipase

Incidence and magnitude of clinically significant changes in Lipase (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Total Protein Creatine Kinase (CK)

Incidence and magnitude of clinically significant changes in Total Protein Creatine Kinase (CK) (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Creatine kinase - cardiac muscle isoenzyme (CK-MB)

Incidence and magnitude of clinically significant changes in Creatine kinase - cardiac muscle isoenzyme (CK-MB) (U/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Troponin T

Incidence and magnitude of clinically significant changes in Troponin T (ng/L).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Prothrombin Time (PT)

Incidence and magnitude of clinically significant changes in Prothrombin Time (PT) (Sec).

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in INR (if under VKA Therapy)

Incidence and magnitude of clinically significant changes in INR (if under VKA Therapy)

Time frame: At the end of Cycle 1 (28 days)

Expansion part: clinically significant changes in Activated Partial Thromboplastin Time (aPTT)

Incidence and magnitude of clinically significant changes in Activated Partial Thromboplastin Time (aPTT) (Sec).

Time frame: At the end of Cycle 1 (28 days)