ANZCTR - Registration

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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]

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Malignant Mesothelioma

Non small cell lung cancer

Condition category

Condition code

Cancer

Lung - Mesothelioma

Cancer

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]

Treatment: Drugs

Comparator / control treatment

No comparator, single arm

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

At baseline, weekly whilst receiving chemotherapy, and at 90-day follow-up visit.

Secondary outcome [1]

Overall survival

Timepoint [1]

Until time of death, or 90 days (+/- 7 days) after end of cycle 6.

Secondary outcome [2]

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]

At baseline, weekly whilst receiving chemotherapy treatment, and at 90-day post treatment follow-up visit

Secondary outcome [3]

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]

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]

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]

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]

Depletion of cyclin (Ki-67hi) Tregs (assessed by FACS analysis)

Timepoint [5]

At baseline, weekly whilst receiving chemotherapy, and at 90-day follow-up visit.

Secondary outcome [6]

Change in antigen-specific CD8+ T-cell responses (assessed by FACS analysis)

Timepoint [6]

At baseline, weekly whilst receiving chemotherapy, and at 90-day follow-up visit.

Secondary outcome [7]

Assessment of CD8+ memory T-cell reactivation (assessed by FACS analysis)

Timepoint [7]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council (NHMRC)

Address [1]

GPO Box 1421
CANBERRA ACT 2601

Country [1]

Australia

Primary sponsor type

Hospital

Name

Sir Charles Gairdner Hospital

Address

Hospital Avenue
NEDLANDS WA 6009

Country

Australia

Secondary sponsor category [1]

University

Name [1]

University of Western Australia

Address [1]

School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
4th Floor, G-Block
Hospital Avenue
NEDLANDS WA 6009

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sir Charles Gairdner Hospital Human Research Ethics Committee

Ethics committee address [1]

Sir Charles Gairdner Hospital
Hospital Avenue
NEDLANDS   WA  6009

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

15/01/2009

Ethics approval number [1]

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

Address

Country

Phone

Fax

Contact person for public queries

Name

Yvonne Demelker

Address

School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
4th Floor, G-Block
Hospital Avenue
NEDLANDS WA 6009

Country

Australia

Phone

+61 8 9346 2186 / +61 404 024 863 (09.00 - 17.00 local time)

Fax

+61 8 9346 2816

yvonned@cyllene.uwa.edu.au

Contact person for scientific queries

Name

A/Prof Anna Nowak

Address

School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
4th Floor, G-Block
Hospital Avenue
NEDLANDS WA 6009

Country

Australia

Phone

+61 8 9346 2098

Fax

+61 8 9346 2816

anowak@cyllene.uwa.edu.au

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

Source	Title	Year of Publication	DOI
Embase	Dexamethasone co-medication in cancer patients undergoing chemotherapy causes substantial immunomodulatory effects with implications for chemo-immunotherapy strategies.	2016	https://dx.doi.org/10.1080/2162402X.2015.1066062
Embase	Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment.	2019	https://dx.doi.org/10.1080/2162402X.2019.1641390
Embase	A phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers.	2021	https://dx.doi.org/10.1080/14737140.2021.1882308

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added manually

Documents added automatically