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Trial registered on ANZCTR


Registration number
ACTRN12609000260224
Ethics application status
Approved
Date submitted
17/02/2009
Date registered
13/05/2009
Date last updated
5/07/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
Optimising regulatory T cell depletion with cyclophosphamide in combination with chemotherapy for enhanced anti-tumour immunity in patients with non-small cell lung cancer (NSCLC) and malignant mesothelioma (MM).
Scientific title
In patients with malignant mesothelioma (MM) and non-small cell lung cancer (NSCLC) does low-dose iterative cyclophosphamide in combination with conventionally dosed pemetrexed-based chemotherapy decrease regulatory T cell numbers and increase antigen-specific and non-specific cellular immunity.
Secondary ID [1] 804 0
No
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Mesothelioma 4327 0
Non small cell lung cancer 4328 0
Condition category
Condition code
Cancer 4562 4562 0 0
Lung - Mesothelioma
Cancer 4563 4563 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cyclophosphamide taken orally once daily (dose ranges from 50mg to 150mg and is titrated according to toxicities and nadir blood T-reg % from last cycle chemotherapy) for the first 14 days of each of cycles 2-6. Each cycle is scheduled to last 21 days.
Pemetrexed-based chemotherapy regimens include as follows:
Pemetrexed single agent 500mg/m2 given IV day 1 of each 21 day cycle.
OR
Cisplatin 75 mg/m2 given IV and pemetrexed 500 mg/m2 given IV day 1 of each 21 day cycle.
OR
Carboplatin AUC 4-6 given IV and pemetrexed 500 mg/m2 given IV day 1 of each 21 day cycle.
Patients will receive treatment for a maximum of 6 cycles.
All pemetrexed-containing regimens will be accompanied by vitamin B12 injection 1000IU 9 weekly and folic acid 0.5 mg daily for the duration of chemotherapy and for at least one month following cessation of chemotherapy as per standard practice.
Intervention code [1] 4057 0
Treatment: Drugs
Comparator / control treatment
No comparator, single arm
Control group
Uncontrolled

Outcomes
Primary outcome [1] 5445 0
To assess the depletion of CD25+ Foxp3+ CD4+ Treg cells during/after pemetrexed-based chemotherapy and cyclophosphamide (expressed as the proportion of Foxp3+ CD25+ CD4+ T cells in the total CD4 T cell pool before and after treatment) as assessed with antibody staining of peripheral blood mononuclear cells for markers of T-cell function/activation/proliferation.
Timepoint [1] 5445 0
At baseline, weekly whilst receiving chemotherapy, and at 90-day follow-up visit.
Secondary outcome [1] 9142 0
Overall survival
Timepoint [1] 9142 0
Until time of death, or 90 days (+/- 7 days) after end of cycle 6.
Secondary outcome [2] 9143 0
Safety and adverse events (as measured from patient questionnaires and clinician assessments, and scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0)
Possible adverse events include nausea and vomiting, impairment of fertility, alopecia, haemorrhagic cystitis, infection, hearing loss (cisplatin), and neurotoxicity (cisplatin/pemetrexed)
Timepoint [2] 9143 0
At baseline, weekly whilst receiving chemotherapy treatment, and at 90-day post treatment follow-up visit
Secondary outcome [3] 9144 0
Time to clinical or radiological progression (clinical progression to be confirmed radiologically if possible. Radiological progression to be determined as per Response Evaluation Criteria in Solid Tumours (RECIST) for non-small cell lung cancer, or modified RECIST for malignant mesothelioma)
Timepoint [3] 9144 0
Radiological assessment, after every 2 cycles of chemotherapy, on clinical progression or at least 3 monthly after the completion of protocol treatment until progressive disease.
Secondary outcome [4] 9145 0
Objective tumour response on computerised tomography (CT) scan (as per RECIST for non-small cell lung cancer, and modified RECIST for malignant mesothelioma)
Timepoint [4] 9145 0
CT scan of chest and abdomen at baseline, after every 2 cycles of chemotherapy, on clinical progression or at least 3 monthly after the completion of protocol treatment until progressive disease.
Secondary outcome [5] 241748 0
Depletion of cyclin (Ki-67hi) Tregs (assessed by FACS analysis)
Timepoint [5] 241748 0
At baseline, weekly whilst receiving chemotherapy, and at 90-day follow-up visit.
Secondary outcome [6] 241749 0
Change in antigen-specific CD8+ T-cell responses (assessed by FACS analysis)
Timepoint [6] 241749 0
At baseline, weekly whilst receiving chemotherapy, and at 90-day follow-up visit.
Secondary outcome [7] 241750 0
Assessment of CD8+ memory T-cell reactivation (assessed by FACS analysis)
Timepoint [7] 241750 0
At baseline, weekly whilst receiving chemotherapy, and at 90-day follow-up visits.

Eligibility
Key inclusion criteria
Histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) or malignant mesothelioma (MM) planned for treatment with a pemetrexed-containing regimen.
Treatment of advanced disease with palliative intent.
First or second line treatment.
Measureable or evaluable disease as defined by the RECIST criteria (NSCLC) or Modified RECIST (MM).
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
History of severe autoimmune disease.
Radiotherapy to all areas of measureable disease.
Previous or concurrent malignancy diagnosis (except curatively-treated basal cell carcinoma (BCC) of skin, carcinoma in situ of cervix) unless treated with curative intent more than 5 years before enrolment.
Concomitant requirement for oral corticosteroids for more than 5 days of each treatment cycle.
Concomitant treatment with other investigational agents or immunotherapy.
Pregnant or breast feeding.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2009
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
33
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 4501 0
Government body
Name [1] 4501 0
National Health and Medical Research Council (NHMRC)
Country [1] 4501 0
Australia
Primary sponsor type
Hospital
Name
Sir Charles Gairdner Hospital
Address
Hospital Avenue
NEDLANDS WA 6009
Country
Australia
Secondary sponsor category [1] 4063 0
University
Name [1] 4063 0
University of Western Australia
Address [1] 4063 0
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
4th Floor, G-Block
Hospital Avenue
NEDLANDS WA 6009
Country [1] 4063 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6561 0
Sir Charles Gairdner Hospital Human Research Ethics Committee
Ethics committee address [1] 6561 0
Sir Charles Gairdner Hospital
Hospital Avenue
NEDLANDS WA 6009
Ethics committee country [1] 6561 0
Australia
Date submitted for ethics approval [1] 6561 0
Approval date [1] 6561 0
15/01/2009
Ethics approval number [1] 6561 0
2008-140

Summary
Brief summary
This study looks at the effectiveness of the chemotherapy drug cyclophosphamide in combination with pemetrexed-based chemotherapy in people with advanced malignant mesothelioma or advanced non-small cell lung cancer receiving first or second line palliative treatment. Participants will all receive low-dose repeat treatment with cyclophosphamide in combination with the conventional dose of pemetrexed-based chemotherapy commencing from the second cycle of chemotherapy, up to a maximum of 6 cycles. Patients will be monitored for safety at the beginning of treatment, weekly whilst on treatment, and at 90-days follow-up. The tumour will be assessed on CT scan at baseline, after every 2 cycles of treatment, and at least 3 monthly after the completion of treatment, until any progression of the disease. The study aims to see whether this treatment is effective by improving the way the immune system reacts against the cancer by assessing the number/activation/proliferation of various immune cells from weekly blood tests taken at baseline, weekly whilst on chemotherapy, and at 90-day follow-up visit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29286 0
Address 29286 0
Country 29286 0
Phone 29286 0
Fax 29286 0
Email 29286 0
Contact person for public queries
Name 12533 0
Yvonne Demelker
Address 12533 0
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
4th Floor, G-Block
Hospital Avenue
NEDLANDS WA 6009
Country 12533 0
Australia
Phone 12533 0
+61 8 9346 2186 / +61 404 024 863 (09.00 - 17.00 local time)
Fax 12533 0
+61 8 9346 2816
Email 12533 0
[email protected]
Contact person for scientific queries
Name 3461 0
A/Prof Anna Nowak
Address 3461 0
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
4th Floor, G-Block
Hospital Avenue
NEDLANDS WA 6009
Country 3461 0
Australia
Phone 3461 0
+61 8 9346 2098
Fax 3461 0
+61 8 9346 2816
Email 3461 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
SourceTitleYear of PublicationDOI
EmbaseDexamethasone co-medication in cancer patients undergoing chemotherapy causes substantial immunomodulatory effects with implications for chemo-immunotherapy strategies.2016https://dx.doi.org/10.1080/2162402X.2015.1066062
EmbaseDexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment.2019https://dx.doi.org/10.1080/2162402X.2019.1641390
EmbaseA phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers.2021https://dx.doi.org/10.1080/14737140.2021.1882308
N.B. These documents automatically identified may not have been verified by the study sponsor.