Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12610000405011
Ethics application status
Approved
Date submitted
17/05/2010
Date registered
20/05/2010
Date last updated
2/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
This study is examining the safety and tolerability of a new drug (Everolimus) in combination with chemotherapy in the treatment of relapsed adult acute lymphobastic leukaemia
Scientific title
Phase 1 study investigating the safety and tolerability of RAD001 (Everolimus) in combination with chemotherapy for treatment of relapsed adult acute lymphoblastic leukemia (ALL)
Secondary ID [1] 251782 0
Australasian Leukaemia and Lymphoma Group -ALL7
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
acute lymphobastic leukaemia (ALL) 257002 0
Condition category
Condition code
Cancer 257164 257164 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients suffering from ALL in first or subsequent relapse will start oral RAD001 (everolimus) treatment (either 2.5mg or 5mg depending on which study cohort is open) once daily on day 1 for a total of 18 doses in 18 days in conjunction with the HyperCVAD regimen. Patients achieving complete remission by day 21 of the preceding chemotherapy cycle can proceed with subsequent cycles of the same RAD001 dose and HyperCVAD up to a total of 4 cycles.

The first cohort of 6 patients will receive 2.5mg dose of RAD001. The data of each cohort will be reviewed to assess whether or not subsequent cohorts of patients can be given 2.5mg or 5mg dose of RAD001 or whether the trial should be closed.
Intervention code [1] 256180 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 258048 0
To assess the safety of RAD001 given in combination with the Hyper CVAD regimen in patients with relapsed ALL. The primary measure of safety will be the duration of myelosuppression, as measured by time to recovery to grade 2 neutropenia.
Timepoint [1] 258048 0
Daily evaluations from start of treatment until day 42 of each chemotherapy course
Secondary outcome [1] 263626 0
To document the duration of severe thrombocytopenia defined as platelets <50x10e9/L.
Timepoint [1] 263626 0
Daily evaluations from start of treatment until day 42 of each chemotherapy course
Secondary outcome [2] 263627 0
To document and review the incidence of Grade 3 and 4 non-hematological toxicities.
Timepoint [2] 263627 0
Daily until day 18 following last study treatment and again at day 42 after last study treatment
Secondary outcome [3] 263628 0
To provide estimates of the complete remission (CR) rate, duration of remission and leukemia-free survival (LFS) and overall survival (OS) in patients treated with this combination as assessed by medical investigations consistent with standard of care
Timepoint [3] 263628 0
3 years after patient was registered to trial

Eligibility
Key inclusion criteria
Morphologically and immunophenotypically confirmed diagnosis of precursor B ALL, negative for Philadelphia chromosome/ bcr-abl fusion transcripts, in first or subsequent relapse more than 6 months after starting treatment with a standard combination chemotherapy protocol.

Has provided written informed consent

Must be surgically sterile or female and postmenopausal (ie >12 mths since the last menstrual cycle) or, if capable of parenting a child, must be using medically acceptable and adequate method of contraception while undergoing protocol treatment and until 90 days after the last treatment.

Adequate renal, hepatic and cardiac functions at Screening as defined by:
Serum bilirubin <2.5 x upper limit of normal (ULN)
Serum creatinine < 1.5ULN, unless medically correctable
Adequate cardiac function with left ventricular ejection fraction (LVEF) >40% and no major left ventricular dysfunction

An Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less at Screening
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with other immunophenotypic variants of ALL (precursor T, mature B)

Women who are pregnant or lactating. Women of child-bearing potential must have a negative urine pregnancy test at Screening.

Patients who have relapsed after an allogeneic transplant

Systemic chemotherapy, immunotherapy, approved proteins/antibodies or any investigational agent within 4 weeks prior to commencing study treatment

Radiotherapy within 14 days of commencing study treatment.

Prior therapy with mammalian target of rapamycin (mTOR) inhibitors (sirolimus, temsirolimus, everolimus)
Uncontrolled diabetes mellitus

CYP3A4 enzyme inducing anti-convulsant medication (eg phenytoin, phenobarbital, or carbemazepine), rifampin and rifabutin, and St. John’s Wort less than or equal to 14 days prior to study treatment

Ketoconazole less than or equal to 7 days before study treatment (Note: interaction with topical ketoconazole cannot be excluded).

Known cirrhosis, chronic active hepatitis, or chronic persistent hepatitis

Unresolved toxicities from prior systemic therapy or radiotherapy that, in the opinion of the investigator, does not qualify the patient for study treatment.

Patients with known interstitial lung disease or severely impaired lung function (spirometry and diffusional capacity lung carbon monoxide (DLCO) 50% or less of normal and oxygen saturation of 88% or less at rest on room air).

Patients who have a history of another primary malignant disease, apart from non-melanotic skin cancer or carcinoma in situ of the uterine cervix or any other cancer treated with curative intent >2 years previously without evidence of relapse.

Any uncontrolled clinically significant cardiac disease, arrhythmias or angina pectoris
Active inflammatory bowel disease or other bowel disease causing chronic diarrhoea (defined as common terminology criteria (CTC) grade 2)

Chronic treatment with immunosuppressives

Patients who, in the opinion of the Investigator, have any severe and/or uncontrolled medical conditions or infections that may compromise study data

Untreated or symptomatic Central Nervous System (CNS) leukaemia

Previous adverse reaction to trial drug(s)

Patients with a known history of Human Immunodeficiency Virus (HIV) seropositivity
Uncontrolled Hepatitis B or C infection. Patients positive for Hepatitis B Virus (HBV) (Hepatitis B surface antigen (HBs Ag) that is not due to vaccination, or HBV deoxyribonucleic acid (DNA)) should undergo prophylactic antiviral therapy for 2 weeks prior to the first dose of RAD001, and for 4 weeks following the last dose of RAD001.

Participation in other therapeutic studies in the last 30 days except for studies with a non-medical intervention. Documented evidence of receiving placebo will be required.

Unable to receive treatment at an affiliated Australasian Leukaemia and Lymphoma Group (ALLG) centre

Medical or psychiatric conditions that compromise the patient’s ability to give informed consent or to complete the protocol

Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central registration
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
1/06/2010
Actual
24/04/2012
Date of last participant enrolment
Anticipated
Actual
24/04/2012
Date of last data collection
Anticipated
Actual
23/04/2015
Sample size
Target
20
Accrual to date
Final
1
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 8682 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 16793 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 256886 0
Commercial sector/Industry
Name [1] 256886 0
Novartis Pharmaceuticals Australia Pty Ltd
Country [1] 256886 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Ground Floor, 35 Elizabeth Street * Richmond, VIC 3121
Country
Australia
Secondary sponsor category [1] 256160 0
None
Name [1] 256160 0
Address [1] 256160 0
Country [1] 256160 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258978 0
Western Sydney Local Health District
Ethics committee address [1] 258978 0
Westmead Hospital, Westmead, NSW 2145
Ethics committee country [1] 258978 0
Australia
Date submitted for ethics approval [1] 258978 0
30/05/2010
Approval date [1] 258978 0
30/06/2011
Ethics approval number [1] 258978 0
HREC/10/WMEAD/198 SSA/11/WMEAD/77

Summary
Brief summary
Patients with relapsed ALL will receive 18 days of oral Everolimus (RAD001) in combination with HyperCVAD therapy. The first 6 patients will receive 2.5mg dose of RAD001. The data of these 6 will be reviewed to assess whether or not subsequent patients can progress to 5mg dose of RAD001, or the trial should be closed.
Trial website
Trial related presentations / publications
None
Public notes

Contacts
Principal investigator
Name 30965 0
Prof Ken Bradstock
Address 30965 0
Westmead Hospital, Westmead, NSW 2145
Country 30965 0
Australia
Phone 30965 0
+61-2-9181 4614
Fax 30965 0
Email 30965 0
[email protected]
Contact person for public queries
Name 14212 0
Prof Ken Bradstock
Address 14212 0
Westmead Hospital, Darcy Rd, Westmead, NSW 2145
Country 14212 0
Australia
Phone 14212 0
+61-2-9181 4614
Fax 14212 0
Email 14212 0
[email protected]
Contact person for scientific queries
Name 5140 0
Prof Ken Bradstock
Address 5140 0
Westmead Hospital, Westmead, NSW 2145
Country 5140 0
Australia
Phone 5140 0
+61-2-9181 4614
Fax 5140 0
Email 5140 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.