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Trial registered on ANZCTR


Registration number
ACTRN12613000198729
Ethics application status
Approved
Date submitted
25/01/2013
Date registered
19/02/2013
Date last updated
29/06/2021
Date data sharing statement initially provided
11/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Study of increasing doses of genetically modified GD2-specific T cells in patients with metastatic melanoma and refractory solid tumours
Scientific title
A phase I study of the safety and immune effects of an escalating dose of autologous GD2 chimeric antigen receptor-expressing peripheral blood T cells in patients with GD2-positive metastatic melanoma and refractory solid tumours
Secondary ID [1] 281784 0
Nil known
Universal Trial Number (UTN)
Trial acronym
CARPETS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic melanoma 288105 0
Refractory solid tumours 314386 0
Condition category
Condition code
Cancer 288479 288479 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients who have a Hb greater than or equal to 105g/L and unresectable metastatic melanoma, which is either BRAF gene mutation negative or positive (BRAF V600E/K/R/D mutations) or other GD2-positive malignancies, will be asked to consent to the study.

The patients blood will be tested and if GD2 positive they will be asked to provide a blood sample for generation of the T-cell product, which will take 3 weeks to produce.

Those eligible to receive dabrafenib and trametinib will be given an initial dose of dabrafenib 150 mg bd and trametinib 2mg od whilst the T-cell product is being prepared. These patients will then receive a single intravenous injection of the T-cell product (GD2-iCAR-PBT). The dose of which (Dose level 2 or Dose level 3, as per the information below) will depend upon the cohort to which the patient is assigned.

For patients not receiving dabrafenib and trametinib there is a possibility that they may have an additional two GD2-iCAR-PBT infusions provided certain criteria are met and the Research Ethics Committee gives permission to do so.

Favourable safety data from the first 6 patients enrolled on the CARPETS protocol at dose level 1: 1 x 10^7 cells/m2 has allowed for the following dose levels to go ahead:

Dose level 2: 2 x 10^7 cells/m2
Dose level 3: 1 x 10^8 cells/m2

Intervention code [1] 286327 0
Treatment: Other
Intervention code [2] 286556 0
Treatment: Drugs
Comparator / control treatment
Not Applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 288638 0
1.The feasibility of preparing T cell products for administration to patients receiving vemurafenib will be determined as the frequency of successfully administered products. Acceptable feasibility is defined as the administration to patients of > or equal to 75% of prepared T cells products.
Timepoint [1] 288638 0
End of study
Primary outcome [2] 288639 0
2. The safety profile and dose limiting toxicities of autologous peripheral blood T cells directed to GD2 through their chimeric antigen receptor (GD2-CAR-PBT as the T cell product) in patients receiving vemurafenib for BRAF-mutant and GD2-positive metastatic melanoma.
Major adverse events related to vemurafenib are rash, fatigue and joint pains. Adverse events related to the T-cell product are unknown. All adverse events will be assessed clinically using NCI CTCAE v4.0
Timepoint [2] 288639 0
Study related adverse events and DLTs are recorded 6 weeks from infusion. Adverse event data will be collected at 4, 8 and 12 months post-infusion, then every year to a total of 15 years.
Secondary outcome [1] 300677 0
1. To assess in vivo persistence of infused GD2-iCAR-PBT using laboratory tests on peripheral blood.
Timepoint [1] 300677 0
15 years
Secondary outcome [2] 300678 0
2. To assess tumour infiltration by infused GD2-iCAR-PBT using laboratory tests on melanoma biopsy material.
Timepoint [2] 300678 0
7 weeks
Secondary outcome [3] 300679 0
3. To assess bystander anti-melanoma immune effects of BRAF inhibitor therapy and infused GD2-iCAR-PBT using laboratory tests on peripheral blood.
Timepoint [3] 300679 0
7 weeks
Secondary outcome [4] 300680 0
4. To document persistence of anti-tumour effects after vemurafenib treatment and the infusion of GD2-iCAR-PBT as measured by partial or complete tumour response or stable disease
Timepoint [4] 300680 0
14 weeks

Eligibility
Key inclusion criteria
1. At least 18 years old;

2. Histological diagnosis of small cell lung cancer, triple negative breast cancer, osteosarcoma, Ewing sarcoma, and such soft tissue sarcomas as rhabdomyosarcoma, liposarcoma, fibrosarcoma, synovial sarcoma, pleomorphic undifferentiated sarcoma, and desmoplastic small round cell tumours (DSRCT), or metastatic melanoma (surgically incurable and unresectable stage III or stage IV; AJCC Cancer Staging Manual, 7th edition, 2010) and greater than or equal to 10% GD2 positive cells (by an independent pathologist);

3. Unresectable stage III melanoma must have confirmation from a surgical oncologist. Melanoma will have V600 BRAF gene mutation status determined; V600E, K, R, or D mutations may be eligible for treatment with dabrafenib and trametinib;

4. Must have failed standard therapy;

5. For metastatic melanoma patients, who will not receive dabrafenib and trametinib concurrently with the GD2-iCAR-PBT infusion, standard therapy includes prior use of BRAF and/or MEK inhibitor for PBS-eligible BRAF-mutant melanoma, combination ipilimumab/nivolumab immunotherapy or pembrolizumab or nivolumab monotherapy. Patients who have not previously tolerated dabrafenib and/or trametinib in the adjuvant or metastatic setting are also eligible. Patients in whom re-induction with ipilimumab or pembrolizumab or nivolumab is contra-indicated because of grade 3 or 4 non-endocrine immune-related adverse events are also eligible;

6. Measurable disease by RECIST 1.1;

7. Must be able and willing to provide written informed consent;

8. Eastern Cooperative Oncology Group Performance Status of 0 or 1;

9. Recovered to = Grade 1 from the acute toxic effects of all prior anti-cancer treatment at least a week before entering this study; for prior ipilimumab, nivolumab, or pembrolizumab, the GD2-iCAR-PBT infusion is given 5 half-lives or greater than or equal to 70 days, greater than or equal to 133 days, or greater than or equal to 110 days after the last dose, respectively;

10. Life expectancy of greater than or equal to 12 weeks;

11. Availability of T-cell product that has met batch release criteria including greater than or equal to 20% expression of GD2-iCAR (by flow cytometry) on the autologous PBT;

12. Fertile male patients must use an effective method of contraception during treatment and for 4 months following discontinuation of trametinib in combination with dabrafenib, or for 4 weeks following discontinuation of dabrafenib;

13. Female patients are eligible to enter and participate in the study if they meet the following inclusion criteria:
• Hysterectomised;
• Bilateral oophorectomy (ovariectomy), or
• Bilateral tubal ligation, or
• Post-menopausal (demonstrated total cessation of menses for greater than or equal to 1 year).
For females of childbearing potential, the patient must:
• Have a negative serum pregnancy test at screening, and a negative urine pregnancy test, prior to dosing at each treatment course.
The female patient must also agree to the use of the following contraceptive methods:
An intrauterine device (IUD) with a documented failure rate of less than 1% per year;
Vasectomized partner who is sterile prior to the patient’s entry and is the sole sexual partner for that woman;
Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm;
Complete abstinence from sexual intercourse where the lifestyle of the patient ensures compliance;
Continue these methods of contraception during treatment and for 4 months following discontinuation of trametinib in combination with dabrafenib, or for 4 weeks following discontinuation of dabrafenib.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Evidence of symptomatic CNS lesions as determined by investigator, use of steroids or anti-seizure medications for treatment of brain metastases. Patients with asymptomatic lesions previously irradiated or surgically resected that are radiologically stable are eligible. Patients with incidentally found brain metastasis that are asymptomatic and for which no treatment is planned are also eligible;

2. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count less than or equal to 1.5 x 109/L or platelet count less than or equal to 100 x 109/L (can not be post-transfusion) or hemoglobin less than 90 g/L (can be post-transfusion);

3. Serum bilirubin > 1.5 times the upper limit of normal;

4. In absence of metastases, liver transaminase levels > 2.5 times the upper limit of normal;

5. If metastases are evident, liver transaminase levels > 5 times the upper limit of normal will be acceptable;

6. Creatinine clearance of less than or equal to 50mL/min calculated by Cockcroft-Gault;

7. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. Patients must be able to swallow tablets;

8. Evidence of severe or uncontrolled systemic diseases (e.g., infection requiring treatment with intravenous (IV) antibiotics, unstable or uncompensated respiratory, cardiac [including life threatening arrhythmias], hepatic, or renal disease.

9. Unresolved toxicity greater than or equal to CTC Grade 2 from previous anti-cancer therapy except alopecia (if applicable) unless agreed that the patient can be entered after discussion with the Medical Monitor;

10. Presence of at least grade 2 peripheral neuropathy;

11. Participation in a trial of an investigational agent within the 30 days prior to day 0;

12. Pregnant or breast-feeding females;

13. Patients with an active seizure disorder;

14. History of congenital long QT syndrome, history or presence of clinically significant ventricular or atrial dysrhythmias greater than or equal to Grade 2 (NCI CTCAE Version 4.0);

15. Patients with a corrected QTc interval of greater than 450 ms (males) and 470 ms (females);

16. Evidence of active infection with HIV, hepatitis B, or hepatitis C;

17. Immunosuppressive therapy including corticosteroids within four weeks of screening;

18. Patients with a history of hypersensitivity reactions to murine protein-containing products, dabrafenib, trametinib, or another BRAF or MEK inhibitor;

19. Use of prophylactic low-dose aspirin, NSAIDs, anticoagulants (unless prescribed for venous or arterial thrombo-embolic disease or atrial fibrillation) will be prohibited in patients commencing dabrafenib and trametinib.

20. Patients with a tumour in a location where enlargement could cause airway obstruction;

21. Any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in this trial or which would jeopardise compliance with the protocol.






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)
Patients are allocated sequentially to a dose level. Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be assigned in sequential order.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Dose escalating design.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Descriptive statistics will be used.
Quantitative variables will be described in terms of median, minimum and maximum for each cohort (dose level) and in terms of mean, median, quartiles, minimum and maximum for the overall population. Qualitative variables will be presented in terms of frequency for each cohort and overall.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
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)
SA
Recruitment hospital [1] 14761 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 6179 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 286567 0
Government body
Name [1] 286567 0
NHMRC
Address [1] 286567 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 286567 0
Australia
Funding source category [2] 286569 0
Government body
Name [2] 286569 0
RISS Ltd.
Address [2] 286569 0
GPO Box 5103
Melbourne
VIC 3001
Country [2] 286569 0
Australia
Funding source category [3] 286570 0
Other Collaborative groups
Name [3] 286570 0
Melanoma and Skin Cancer Trials
Address [3] 286570 0
Level 2, 553 St Kilda Road, Melbourne, Victoria 3004
Country [3] 286570 0
Australia
Primary sponsor type
Hospital
Name
Royal Adelaide Hospital Cancer Centre
Address
Royal Adelaide Hospital
Cancer Clinical Trials Unit
Level 6E 351 Desk 37
Port Road
Adelaide
SA 5000
Country
Australia
Secondary sponsor category [1] 285353 0
None
Name [1] 285353 0
Address [1] 285353 0
Country [1] 285353 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295566 0
Royal Adelaide Hospital Research Ethics Committee
Ethics committee address [1] 295566 0
Level 3 Hanson Institute, North Terrace, Adelaide, SA 5000
Ethics committee country [1] 295566 0
Australia
Date submitted for ethics approval [1] 295566 0
12/04/2010
Approval date [1] 295566 0
19/07/2010
Ethics approval number [1] 295566 0
100524

Summary
Brief summary
The main aim of this Phase I study is to assess the safety and immune effects of using autologous peripheral blood T cells in GD2 positive patients with metastatic melanoma or refractory solid tumours. Patients who are BRAF positive will be given being treated with dabrafenib and trametinib. These inhibitors are proving to be effective in the up to 60% of malignant melanomas that are found to have a BRAF mutation. However, drug resistance is emerging and many patients relapse affirming the need for further treatment development.

Who is this study for and who is it open to?
This study is for patients with metastatic melanoma who are BRAF V600E/K/R/D positive or negative, or other GD2-positive malignancies. Those who are BRAF positive must be eligible to receive dabafenib and trametinib Patients who consent to the study will be asked permission to test their archived tissue for GD2 expression. If this test returns a positive result, the patient may then continue with the trial.

What will the patients receive?
BRAF positive patients will receive dabrafenib 150mg bd and trametinib 2mg od during the 3 week period in which the T-cell product is being prepared. Once produced, the T-cell product will be given as a single intravenous infusion at a dose relevant to the cohort that the patient has been assigned to. The patient will then be monitored as per the follow up schedule specified by the study protocol.

For patients who are BRAF negative and not receiving dabrafenib or trametinib, they may potentially receive two further doses of the T-cell product.
Trial website
https://www.masc.org.au/recruiting-trials/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 37082 0
Prof Michael Brown
Address 37082 0
Royal Adelaide Hospital
Cancer Clinical Trials Unit
Level 6E 351 Desk 37
Port Road
Adelaide
South Australia 5000
Country 37082 0
Australia
Phone 37082 0
+61 8 707 42335
Fax 37082 0
Email 37082 0
Michael.Brown@health.sa.gov.au
Contact person for public queries
Name 37083 0
Ms Anne Milton
Address 37083 0
Royal Adelaide Hospital
Cancer Clinical Trials Unit
Level 6E 351 Desk 37
Port Road
Adelaide
South Australia 5000
Country 37083 0
Australia
Phone 37083 0
+61 8 7074 2342
Fax 37083 0
Email 37083 0
Anne.Milton@health.sa.gov.au
Contact person for scientific queries
Name 37084 0
Prof Michael Brown
Address 37084 0
Royal Adelaide Hospital
Cancer Clinical Trials Unit
Level 6E 351 Desk 37
Port Road
Adelaide
South Australia 5000
Country 37084 0
Australia
Phone 37084 0
+61 8 8222 4157
Fax 37084 0
Email 37084 0
Michael.Brown@health.sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Patient data remains de-identified and will not be shared
What supporting documents are/will be available?
No other documents available
Summary results
No Results