Study Evaluating Impact of IL-7 on CD4 Lymphopenia, Risks of Severe Haematological Toxicity and Tumor Progression in Metastatic Breast Cancer Patients

Metastatic Breast Cancer Clinical Trial

Official title:

A Randomised, Multicentric, Phase 2a Study Evaluating the Impact of an Immunotherapy by IL-7 on CD4 Lymphopenia, Risks of Severe Haematological Toxicity and Tumor Progression in Metastatic Breast Cancer Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01368107
• Other study ID #: ELYPSE 7
• Secondary ID: 2011-000226-30
• Status: Completed
• Phase: Phase 2
• First received: June 6, 2011
• Last updated: February 6, 2015
• Start date: June 2011
• Est. completion date: June 2014

Study information

• Verified date: December 2013
• Source: Centre Leon Berard
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to evaluate the impact of an immunotherapy by IL-7 on CD4 lymphopenia, risks of severe haematological toxicity and tumor progression in metastatic breast cancer patients.

The primary objective is to determine the optimal schedule to deliver CYT107 during chemotherapy based on restoration of CD4 count.

This study is a phase II, randomised, double-blind, placebo-controlled, single-centre.

24 patients will be included in the study.

Description:

A key secondary objective is to determine if CYT107 treatment enables to reduce the incidence of severe haematological toxicity (any type of haematological toxicity Grade ≥ 3) post-chemotherapy.

Other secondary objectives are to assess the impact of CYT107 treatment on the following parameters:

• Overall incidence of side effects (any type any grade)

• Progression-free survival (PFS)

• Compliance to chemotherapy regimen (dose intensity, number of chemotherapy cycles).

• CD4 lymphopenia over the study period

Exploratory biological markers

A series of biomarkers analyses will be performed to evaluate if CYT107 treatment will:

• selectively stimulate the proliferation and activation of peripheral immune subsets (analysis of phenotype and activation status of peripheral immune e sub-populations)

• selectively improve the functional response of T cells, DC subsets and NK cells.

• is able to revert tolerogenic immune burden to increase specific anti-tumor response (measure of antigen specific CD8 response, measure of cytokine plasmatic levels)

• enable to increase TCR diversity (analysis of combinatorial diversity).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: June 2014
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Female aged more than 18 years

• Histologic diagnosis of metastatic breast cancer to be treated with capecitabine at study entry. NB: Patients previously treated with capecitabine are eligible only if more than 6 months have elapsed since the last capecitabine intake.

• Lymphopenic (i.e. with at least one value of lymphocyte count 1500/µL within 15 days before Day 0).

• Performance status ECOG of 0, 1,2 or 3

• Life expectancy = 6months

• Adequate bone marrow, hepatic and renal function as follows:

• Neutrophils = 1,000/µL

• Platelets = 100 109/µL

• ASAT, ALAT, or Alkaline Phosphatase = 2.5 x ULN

• Total Bilirubin = 1.5 x ULN

• INR = 1.5

• Calculated creatinin clearance = 60mL/min (Cockcroft formula or MDRD formula for patients older than 65 years old)- Ability to understand and sign informed consent

• Covered by a medical insurance.

Exclusion Criteria:

• Prior history of other malignancies other than breast cancer (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the subjects has been free of the disease for at least 3 years.

• No resolution of specific toxicities related to any prior anti-cancer therapy to Grade =2 according to the NCI CTCAE v.4.0 (except lymphopenia, alopecia and neuropathy)

• Wash out period of less than 5 times the half-life of previous anti-cancer treatment before study entry, except if previous chemotherapy treatment before study entry. NB: For patient previously treated by hormonotherapy, a wash out period of 1 week will be sufficient

• Uncontrolled hypertension (i.e., resting systolic blood pressure greater than140 mmHg or resting diastolic blood pressure greater than 90 mmHg), despite pharmacologic antihypertensive treatment, confirmed with a second blood pressure measurement done later in the same day

• History of lymphoid malignancy (e.g. Hodgkin disease, non Hodgkin lymphoma, Leukemia).

• History of splenectomy or hematologic disease associated with hypersplenism, such as gamma or beta-thalassemia, hereditary spherocytosis, Gaucher's disease, or autoimmune hemolytic anemia.

• Any cardiac, pulmonary, thyroid, renal, hepatic, neurological severe/uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol

• Any history of severe auto-immune disease

• Hepatitis B antigen (HBs Ag) positive, Hepatitis C (HCV Ab) antibody positive or HCV RNA detectable

• Documented HIV-1 positivity

• History of cardiovascular disorders grade >2 (NYHA) within 6 months preceding the inclusion

• Active uncontrolled viral, fungal or bacterial infection

• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements (participants must agree to refrain from substance abuse use during the entire course of the study)

• Pregnant or breast-feeding women

• No use of effective birth control methods for women of childbearing potential

• Any contraindications to capecitabine treatment (refer to Xeloda SPC Appendix 11) and to any other anti-cancer treatment authorized as per protocol (refer to respective SPC for specific contraindications)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Lymphopenia
• Metastatic Breast Cancer

Intervention

Drug:
• placebo
Placebo before the 1st (D0, D7, D14)and during the 3rd CT cycle (D57, D64, D71)
• interleukin 7
patients will receive an induction cycle of CYT107 (10µg/kg/week subcutaneously for 3 weeks) before the 1st CT cycle (D0, D7, D14) and the placebo during the 3rd CT cycle (D57, D64, D71)
• interleukin 7
patients will receive the placebo before the 1st CT cycle (D0, D7, D14) and a delayed treatment with CYT107 (10µg/kg/week subcutaneously for 3 weeks) during the 3rd CT cycle (D57, D64, D71)
• interleukin 7
patients will receive an induction cycle of CYT107 (10µg/kg/week subcutaneously for 3 weeks) before the 1st CT cycle (D0, D7, D14) and a maintenance cycle of IL-7 (10µg/kg/week subcutaneously for 3 weeks) during the 3rd CT cycle (D57, D64, D71)

Locations

Country	Name	City	State
France	Centre Leon Berard	Lyon
France	Institut Curie	Paris
France	Institut Gustave Roussy	Villejuif

Sponsors (3)

Lead Sponsor	Collaborator
Centre Leon Berard	Cytheris, Inc., Ministry of Health, France

Country where clinical trial is conducted

France, 

References & Publications (30)

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Marec-Berard P, Blay JY, Schell M, Buclon M, Demaret C, Ray-Coquard I. Risk model predictive of severe anemia requiring RBC transfusion after chemotherapy in pediatric solid tumor patients. J Clin Oncol. 2003 Nov 15;21(22):4235-8. — View Citation

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Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE, Dissanayake D, Dhanji S, Nguyen LT, Gronski MA, Morre M, Assouline B, Lahl K, Sparwasser T, Ohashi PS, Mak TW. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enha — View Citation

Ray-Coquard I, Borg C, Bachelot T, Sebban C, Philip I, Clapisson G, Le Cesne A, Biron P, Chauvin F, Blay JY; ELYPSE study group. Baseline and early lymphopenia predict for the risk of febrile neutropenia after chemotherapy. Br J Cancer. 2003 Jan 27;88(2): — View Citation

Ray-Coquard I, Cropet C, Van Glabbeke M, Sebban C, Le Cesne A, Judson I, Tredan O, Verweij J, Biron P, Labidi I, Guastalla JP, Bachelot T, Perol D, Chabaud S, Hogendoorn PC, Cassier P, Dufresne A, Blay JY; European Organization for Research and Treatment — View Citation

Ray-Coquard I, Le Cesne A, Rubio MT, Mermet J, Maugard C, Ravaud A, Chevreau C, Sebban C, Bachelot T, Biron P, Blay JY. Risk model for severe anemia requiring red blood cell transfusion after cytotoxic conventional chemotherapy regimens. The Elypse 1 Stud — View Citation

Rosenberg SA, Sportès C, Ahmadzadeh M, Fry TJ, Ngo LT, Schwarz SL, Stetler-Stevenson M, Morton KE, Mavroukakis SA, Morre M, Buffet R, Mackall CL, Gress RE. IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of — View Citation

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* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	to determine the optimal schedule to deliver CYT107 during chemotherapy based on restoration of CD4 count	Evolution of CD4 count from Day 0 to Week 11 with repeated measures from D0 to W12 (D0, D21, D57, D78).	after 11 weeks of treatment	No
Secondary	to determine if CYT107 treatment enables to reduce the incidence of severe haematological toxicity (any type of haematological toxicity Grade = 3) post-chemotherapy		at the end of study M12	Yes
Secondary	To assess the impact of CYT107 on progression-free survival	Time from randomisation to first evidence of progression or death of any cause.	at the end of study (M12)	No
Secondary	To assess the impact of CYT107 on compliance to chemotherapy regimen (dose intensity, number of chemotherapy cycles).	Number of CT cycles, CT dose delays and/or reduction, CT discontinuation	at the end of study (M12)	No
Secondary	To assess the impact of CYT107 on CD4 lymphopenia over the study period	Evolution of CD4 count from Day 0 to end of study visit	at the end of study (M12)	No
Secondary	to evaluate if CYT107 treatment will selectively stimulate the proliferation and activation of peripheral immune subsets (analysis of phenotype and activation status of peripheral immune e sub-populations)	Measure of frequency and activation status of circulating immune subpopulations on fresh whole blood. Multi-parametric marker sets (6-8 markers) will be used to analyse phenotype of immune subpopulations (TCD4+, TCD8+, Treg, T, NK, DC) and their activation status (PD1, ICOS, CD39, CD73, CD62L, CCR7, CD45RO, CD45RA, CD86).	D0, D21, D57, D78 and at end of study M12	No
Secondary	to evaluate if CYT107 treatment will selectively improve the functional response of T cells, DC subsets and NK cells	Analysis of the functional response of T cells, DC subsets and NK cells	D0, D21, D57, D78 and at the end of study M12	No
Secondary	to evaluate if CYT107 treatment will is able to revert tolerogenic immune burden to increase specific anti-tumor response (measure of antigen specific CD8 response, measure of cytokine plasmatic levels)	Analysis of tumor associated antigen (TAA) specific CD8 responses; Quantification of circulating cytokines including mainly, but not limited to, IL-6, IL-2, IFN, VEGF, TNF, IL-15,F FGF using Luminex technology and VEGF, TGF, IL-7R by Elisa.	D0, D21, D57, D78 and at the end of study M12	No
Secondary	to evaluate if CYT107 treatment will enable to increase TCR diversity (analysis of combinatorial diversity).	Evaluation of T cell receptor diversity using ImmuneTraCkeR test and Constel'ID software (ImmunID Technologies, Grenoble, France).	D0, D21, D57, D78 and at the end of study M12	No
Secondary	To assess the impact of CYT107 treatment on overall incidence of side effects	Number of patients with AEs (any type any grade) using NCI-CTCAE scale (version 4.0) from D0 to W12	after 12 weeks of treatment	Yes