CLO21800205

Genzyme Corporation

500 Kendall Street, Cambridge, MA, United States, 02142

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

No

No

Yes

Final

16 Aug 2010

No

Yes

25 Nov 2009

No

The primary objective for the Phase I portion of the study is to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and the recommended Phase II dose (RP2D) of clofarabine when used in combination with etoposide and cyclophosphamide and to assess the feasibility and safety of this combination regimen to treat children with refractory or relapsed acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML).

Paediatric subjects: The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort. Adult Subjects: Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the SanofiAventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

11 Mar 2006

No

No

United States: 50

50

0

0

0

0

1

24

19

6

0

0

Overall Study (overall period)

Not applicable

Yes

Clofarabine

Clolar, Evoltra

Concentrate for solution for infusion

Intravenous use

20‑40 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle as the first of the three IV interventions administered. Maximum of 8 cycles was given.

Etoposide

Eposin

Concentrate for solution for infusion

Intravenous use

75-100 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle following clofarabine therapy. Maximum of 8 cycles was given.

Cyclophosphamide

Endoxan, Revimmune, Cytoxan

Concentrate for solution for infusion

Intravenous use

340‑440 mg/m²/day as 30-60 minute intravenous (IV) infusion daily for 5 days of a 28 day cycle following the other two interventions. Maximum of 8 cycles was given.

Clofarabine

Clolar, Evoltra

Concentrate for solution for infusion

Intravenous use

20‑40 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle as the first of the three IV interventions administered. Maximum of 8 cycles was given.

Etoposide

Eposin

Concentrate for solution for infusion

Intravenous use

75-100 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle following clofarabine therapy. Maximum of 8 cycles was given.

Cyclophosphamide

Endoxan, Revimmune, Cytoxan

Concentrate for solution for infusion

Intravenous use

340‑440 mg/m²/day as 30-60 minute intravenous (IV) infusion daily for 5 days of a 28 day cycle following the other two interventions. Maximum of 8 cycles was given.

Phase 1: Clofarabine, Etoposide, Cyclophosphamide

Phase 2: Clofarabine, Etoposide, Cyclophosphamide

Phase 1: Clofarabine, Etoposide, Cyclophosphamide

Phase 2: Clofarabine, Etoposide, Cyclophosphamide

Phase 1 - Cohort 1

Subjects were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 340 mg/m^2.

Phase 1 - Cohort 2

Subjects were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 440 mg/m^2.

Phase 1 - Cohort 3

Subjects were treated with clofarabine 20 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2.

Phase 1 - Cohort 4

Subjects were treated with clofarabine 30 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2.

Phase 1 - Cohort 5

Subjects were treated with clofarabine 40 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2.

The MTD was to be the highest dose level of clofarabine in combination with etoposide and cyclophosphamide that caused <= 1 of 6 subjects to experience a dose limiting toxicity (DLT) with the next higher dose level having at least 2 of 3 or 2 of 6 subjects experiencing a DLT. The MTD would be used as the recommended phase 2 dose (RP2D). If the MTD could not be determined, then the target dose of clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 as taken by Cohort 5 was to become the RP2D. The rating scale used is 0 = not the MTD, 1 = the MTD. All phase 1 subjects.

Primary

Up to Day 42 (Phase 1 portion of study)

The number of subjects in each cohort that had dose limiting toxicity is summarized. Toxicities were reviewed by an independent Data Safety Monitoring Board (DSMB) who determined if additional subjects should be added to the cohort and the criteria for escalating to the next cohort. All phase 1 subjects

Primary

Up to Day 42 (Phase 1 portion of study)

Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with <5% blasts, and platelet (plt)/ANC recovery: ≥75/ ≥0.75 [x 10^9/L] 2) CR in absence of plt recovery (CRp): plt ≥20 to <75 x 10^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with <5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR. All phase 2 subjects.

Primary

Approximately 28-56 days (Phase 2 portion of study)

Number of subjects with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) and relationship to study drug. The severity scale is: > Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE. All phase 1 subjects.

Secondary

Up to 9.5 months (Phase 1 portion of study)

Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with <5% blasts, and platelet (plt)/ANC recovery: ALL ≥75/ ≥0.75 [x 10^9/L]; AML ≥100/ ≥1.0 [x 10^9/L] 2) CR in absence of plt recovery (CRp): ALL plt ≥20 to <75 x 10^9/L; AML plt ≥20 to <100 x 10^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with <5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR. All phase 1 subjects.

Secondary

Approximately 2 months (Phase 1 portion of study)

The weeks between start of intervention and remission as assessed by the investigator in Phase 1. Subjects who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included. Subjects in phase 1 who had an overall remission.

Secondary

up to 8 weeks (Phase 1 portion of study)

Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks. Phase 1 subjects who achieved overall remission. Data are censored at date of last known follow-up visit.

Secondary

Up to 2 years (Phase 1 portion of study)

Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks. All phase 1 subjects. Data are censored at date of last known follow-up visit.

Secondary

Up to 2 years (Phase 1 portion of study)

Number of subjects with event-free survival at four months post first dose of therapy. A subject is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse. All subjects.

Secondary

4 months (Phase I portion of study)

Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks. All phase 1 subjects

Secondary

Up to 2 years (Phase 1 portion of study)

Number of subjects with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) and relationship to study drug. The severity scale is: > Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE. All phase 2 subjects

Secondary

Up to 9.5 months (Phase 2 portion of study)

The weeks between start of intervention and remission as assessed by the investigator in Phase 2. Subjects who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included. Subjects in phase 2 who had an overall remission.

Secondary

up to 8 weeks (Phase 2 portion of study)

Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks. Phase 2 subjects who achieved overall remission. Data are censored at date of last known follow-up visit. 99999 represents data not estimable because values are mostly censored. Subjects with longer DORs have not relapsed, progressed, or died, therefore the upper confidence limit cannot be estimated.

Secondary

Up to 2 years (Phase 2 portion of study)

Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks. All phase 2 subjects. Data are censored at date of last known follow-up visit.

Secondary

Up to 2 years (Phase 2 portion of study)

Number of subjects with event-free survival at four months post first dose of therapy. A subject is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse. All subjects.

Secondary

4 months (Phase 2 portion of study)

Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks. All phase 2 subjects. Data are censored at date of last known follow-up visit.

Secondary

Up to 2 years (Phase 2 portion of study)

Reported AEs are Treatment emergent adverse events and death occurred in Phase 1 from day 1 up to 9.5 months. Phase 2 also lasted up to 9.5 months and started after Phase 1.

In the event a single subject has experienced both a serious and a non-serious form of the same adverse event term, the subject has been included in the numerator ("number of affected subjects") of adverse event tables.

13.0

Phase 1 - Cohort 1

Phase 1 - Cohort 2

Phase 1 - Cohort 3

Phase 2: Clofarabine, Etoposide, Cyclophosphamide

Phase 1 - Cohort 5

Phase 1 - Total

Phase 1 - Cohort 4