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Trial registered on ANZCTR


Registration number
ACTRN12618001236280
Ethics application status
Approved
Date submitted
19/06/2018
Date registered
23/07/2018
Date last updated
16/09/2019
Date data sharing statement initially provided
18/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors
Scientific title
A Randomized Phase III Trial Comparing Conventional-Dose Chemotherapy Using Paclitaxel, Ifosfamide, and Cisplatin (TIP) With High-Dose Chemotherapy Using Mobilizing Paclitaxel Plus Ifosfamide Followed by High-Dose Carboplatin and Etoposide (TI-CE) as First Salvage Treatment in Relapsed or Refractory Germ Cell Tumors
Secondary ID [1] 295071 0
ClinicalTrials.gov: NCT02375204
Secondary ID [2] 295072 0
Alliance for Clinical Trials in Oncology: A031102
Secondary ID [3] 295074 0
NCI-2014-01696 (Registry Identifier: NCI Clinical Trial Reporting Program)
Universal Trial Number (UTN)
U1111-1215-1783
Trial acronym
TIGER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Germ Cell Tumor 308116 0
Teratoma 308117 0
Choriocarcinoma 308118 0
Germinoma 308119 0
Mixed Germ Cell Tumor 308120 0
Yolk Sac Tumor 308121 0
Childhood Teratoma 308122 0
Malignant Germ Cell Neoplasm 308123 0
Extragonadal Seminoma 308124 0
Non-seminomatous Germ Cell Tumor 308125 0
Seminoma 308126 0
Cancer 308145 0
Condition category
Condition code
Cancer 307157 307157 0 0
Testicular
Cancer 307180 307180 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm A: TIP

Arm A therapy will consist of 4 cycles of Paclitaxel, Ifosfamide, Cisplatin and Pegylated G-CSF administered every 21 days (+/- 4 days) as follows:

- Paclitaxel: 250 mg/m^2 IV over 24 hours on Day 1
*Premedication (refers to the minimum allowed but institutional protocols administering
additional or more intensive prophylaxis are allowed)
*Dexamethasone: 20 mg orally approximately 14 (12-24) hours and 7 (6-9) hours before
paclitaxel (taken by the patient at home the night before and morning of day 1 or 20 mg
IV 30-60 minutes prior to the initiation of the paclitaxel infusion.
*Diphenhydramine: 25 to 50 mg IVPB 30-60 minutes prior to paclitaxel. Oral can be
substituted but must be given 60 minutes prior to paclitaxel. An equivalent H1 blocker
(e.g., hydroxyzine) can be substituted for diphenhydramine.
*H2 blocker: Ranitidine, Cimetidine, and Famotidine are acceptable, given orally 60
minutes prior or by IVPB 30-60 minutes prior to paclitaxel.

- Ifosfamide: 1500 mg/m^2 IV daily on Days 2-5 with mesna protection
*Mesna: 1500 mg/^2 should be given to match the ifosfamide dose, either mixed 1:1 with
ifosfamide or simultaneous in a separate bag or pre- or post- ifosfamide and hydration.

- Cisplatin 25 mg/m^2 IV daily on Days 2-5

- Pegylated Granulocyte Colony Stimulating Factor (G-CSF) 6 mg subcutaneous on Day 6, 7
or 8 (as determined by the investigator).

- Hydration guidelines: At least one liter of normal saline prior to the initiation of cisplatin.
Hydration should consist of normal saline infused at 100 mL/hr and continue throughout the 5 days of chemotherapy. At least one liter of normal saline should be given post the last dose of cisplatin. Hydration can be modified per institutional guidelines.

- Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or
Ciprofloxacin 500mg twice daily by mouth should be given from days 7 to 13 of each cycle for infectious prophylaxis.

Arm B: TI-CE

Arm B therapy will consist of 2 cycles (cycles 1-2) of Paclitaxel, Ifosfamide, and G-CSF folled by leukapheresis every 14 days. Then 3 cycles (cycles 3-5) of carboplatin, etoposide, stem cell reinfusion, and Pegylated G-CSF every 21 days.

CYCLE 1 (14-21 days):-

- Paclitaxel 200 mg/m^2 IV over 3 hours on Day 1 including pre-medication as defined above in Arm A (i.e. dexamethasone, diphenhydramine and H2 blocker)

- Ifosfamide 2000 mg/m^2 IV daily on Days 1-3 with mesna protection
*Mesna: 2000 mg/^2 should be given to match the ifosfamide dose, either mixed 1:1 with
ifosfamide or simultaneous in a separate bag or pre- or post- ifosfamide and hydration.

- G-CSF 10 µg/kg subcutaneously daily on Days 3-15 (cycle 1) and Days 3-14 (cycle 2) or pegylated G-CSF 6 mg subcutaneous on Day 4 or 6 (cycle 1) and Day 4 or 5 (cycle 2)

- Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or
Ciprofloxacin 500mg twice daily by mouth should be given from days 6 to 10.

- Leukapheresis starting on day 11 (or earlier based on assessment of circulating CD34+ cells at the discretion of the investigator) and continued daily until reaching the target CD34+ cell collection of = 8 x 106 CD34+ cells/kg) or day 15, whichever occurs first.

CYCLE 2 (14-21 days):-

- Paclitaxel 200 mg/m2 IV over 3 hours on Day 1 including pre-medication as defined above (i.e. dexamethasone, diphenhydramine and H2 blocker)

- Ifosfamide 2000 mg/m^2 IV daily on Days 1-3 with mesna protection
*Mesna: 2000 mg/^2 should be given to match the ifosfamide dose, either mixed 1:1 with
ifosfamide or simultaneous in a separate bag or pre- or post- ifosfamide and hydration.

- G-CSF 10 µg/kg subcutaneously daily on Days 3-15 (cycle 1) and Days 3-14 (cycle 2) or pegylated G-CSF 6 mg subcutaneous on Day 4 or 6 (cycle 1) and Day 4 or 5 (cycle 2)

- Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or
Ciprofloxacin 500mg twice daily by mouth should be given from days 6 to 10.

- Leukapheresis starting on day 11 (or earlier based on assessment of circulating CD34+ cells at the discretion of the investigator) and continued daily until reaching the target CD34+ cell collection of = 8 x 106 CD34+ cells/kg) or day 15, whichever occurs first.

CYCLE 3-5 ( 21- 28 days each)

Cycle 3 should start between 14 and 21 days after the start of cycle 2, with goal of starting as close to 14 days as possible.

- Carboplatin: Area Under-the-Curve=8 daily intravenously on Days 1-3 (dose to be calculated by investigator depending on age of patient).

- Etoposide 400 mg/m^2 daily on Days 1-3
*Hydration: dilute etoposide in 0.9 NS during infusion with hydration according to
institution guidelines.

- Stem cell re-infusion on day 5 (= 2 x 106 CD34+ cells/kg)
*Hydration: NS 300 mL/hr 3 hours prior to re-infusion and for a minimum of 3 hours
post re-infusion.

- Pegylated G-CSF 6 mg subcutaneously 6 to 24 hours after completion of stem cell re-infusion. Or G-CSF at approximately 5 µg/kg daily on Days 5-15

- Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or Ciprofloxacin 500mg twice daily by mouth should be given from days 7 to 15 or ANC recovery to greater than or equal to 1.0.

- Anti-fungal prophylaxis: is not required but may be given at the discretion of the treating investigator and institution

- Additional antimicrobial prophylaxis (PCP, antiviral, antifungal, etc.) is not required but may
be given at the discretion of the treating investigator and institution

All medication will be administered under the supervision of a medical clinician or research nurse. This will ensure that all patients adhere to administered study medication.
Intervention code [1] 301402 0
Treatment: Drugs
Intervention code [2] 301418 0
Treatment: Other
Comparator / control treatment
The Control Group will be those allocated to Arm A - TIP

Control group
Active

Outcomes
Primary outcome [1] 306127 0
Overall survival
Timepoint [1] 306127 0
Overall survival will be defined from date of randomisation to death due to any cause. For surviving patients, overall survival will be censored on the date the patient was last know to be alive as assessed at 3 years post treatment commencement.
Secondary outcome [1] 347631 0
Progression free survival (PFS).
PFS will be measured via medical records kept at the hospital where the patient was treated.
Timepoint [1] 347631 0
Progression Free Survival: PFS will be measured from the date of randomization to date of
progression or death due to any cause, whichever occurs first.
Secondary outcome [2] 347632 0
Favorable Response Rate
Timepoint [2] 347632 0
Favorable Response Rate (FRR): The favorable response rate (FRR) will be defined as the
proportion of patients achieving either a complete response (CR) or partial response with
normal serum tumor markers (PR-neg) at the time of the end of treatment assessment (Arm A: less than or equal to 28 days from last day of cisplatin; Arm B: less than or equal to 28 days from the last stem cell re-infusion).
Secondary outcome [3] 347633 0
Treatment related mortality
Timepoint [3] 347633 0
Treatment-related mortality: Treatment-related mortality will be defined as any death
occurring during protocol chemotherapy, or within 30-days following the end of this
treatment.
Secondary outcome [4] 347634 0
Toxicity
Timepoint [4] 347634 0
Toxicities will be evaluated and recorded based on the NCI common toxicity criteria (CTCAE v4.0). They will be described by frequency and grade, by cycle and over all cycles, with the maximum grade over all cycles used as the summary measure for each patient.
Secondary outcome [5] 347635 0
To prospectively evaluate the IPFSG scoring system as a predictor of outcome to initial salvage therapy in patients with relapsed or refractory GCT. In this trial, randomisation will be stratified by a modification of the IPFSG category and we will prospectively evaluate whether or not actual outcomes vary by risk group in the appropriate manner (low risk patients have higher OS than high-risk group).
Timepoint [5] 347635 0
3 years post-registration

Eligibility
Key inclusion criteria
1. Documentation of Disease

- Histologic Documentation: Confirmation of GCT histology (both seminoma and nonseminoma) on pathologic review at the center of enrollment.
- Tumor may have originated in any primary site. NOTE: In rare circumstances, patients will be allowed to enroll even if a pathological diagnosis may not have been established.
- This would require a clinical situation consistent with the diagnosis of GCT (testicular, peritoneal, retroperitoneal or mediastinal mass, elevated tumor marker levels {HCG greater than or equal to 500; AFP greater than or equal to 500} and typical pattern of metastases)

2. Evidence of Disease

- Must have evidence of progressive or recurrent GCT (measurable or non-measurable) following one line of cisplatin-based chemotherapy, defined as meeting at least one of the following criteria:

* Tumor biopsy of new or growing or unresectable lesions demonstrating viable non-teratomatous GCT (enrollment on this study for adjuvant treatment after macroscopically complete resection of viable GCT is not allowed). In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for the study.
* Consecutive elevated serum tumor markers (HCG or AFP) that are increasing. Increase of an elevated LDH alone does not constitute progressive disease.
* Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to increase.

3. Prior Treatment

- Must have received 3-6 cycles of cisplatin-based chemotherapy as part of first-line (initial) chemotherapy.

* Prior POMBACE, CBOP-BEP, or GAMEC are allowed.
* Note: For patients requiring immediate treatment, 1 cycle of conventional-dose salvage chemotherapy is allowed. Therefore, these patients may have received 7 prior cycles of chemotherapy. 6 cycles as part of first-line chemotherapy and 1 cycle of salvage conventional chemotherapy.

- No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy)

* Definition of one line of chemotherapy: One line of therapy can in some cases consist of 2 different cisplatin-based treatment combinations, provided there is no disease progression between these two regimens.
* Prior treatment with carboplatin as adjuvant therapy is allowed, provided patients meet other eligibility criteria (e.g., the patient has also received 3-4 cycles of cisplatin-based chemotherapy).
* Prior treatment with 1-2 cycles of BEP or EP as adjuvant chemotherapy for early stage GCT is allowed, provided the patient also received 3-4 cycles of BEP or EP again at relapse. Patients treated with 3-4 cycles of VIP at relapse following 1-2 cycles of BEP/EP are not eligible as this would be considered more than 1 line of prior therapy.

- No prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue)
- No prior treatment with TIP with the exception when given as a bridge to treatment on protocol for patients with rapidly progressive disease who cannot wait to complete the eligibility screening process. Only one cycle is allowed.
- No concurrent treatment with other cytotoxic drugs or targeted therapies.
No radiation therapy (other than to the brain) within 14 days of day 1 of protocol chemotherapy except radiation to brain metastases, which must be completed 7 days prior to start of chemotherapy.
- No previous chemotherapy within 17 days prior to enrollment. A minimum of three weeks after the last day of the start of the previous chemotherapy regimen before the first day of chemotherapy on study protocol.
- Must have adequate recovery from prior surgery (eg, healed scar, resumption of diet)

4. Age more than 14 years or above (more than 18 years or above in Germany)

5. ECOG Performance Status 0 to 2

6. Male gender

7. Required Initial Laboratory Values:

- Absolute Neutrophil Count (ANC) greater than or equal to 1,500/mm^3
- Platelet Count greater than or equal to 100,000/mm^3
- Calculated creatinine clearance greater than or equal to 50 mL/min
- Bilirubin less than or equal to 2.0 x upper limits of normal (ULN)
- AST/ALT less than or equal to 2.5 x upper limits of normal (ULN)

8. No concurrent malignancy other than non-melanoma skin cancer, superficial noninvasive (pTa or pTis) TCC of the bladder, contralateral GCT, or intratubular germ cell neoplasia. Patients with a prior malignancy, but at least 2 years since any evidence of disease are allowed.

9. Negative Serology (antibody test) for the following infectious diseases:

- Human Immunodeficiency Virus (HIV) type 1 and 2
- Human T-cell Leukemia Virus (HTLV) type 1 and 2 (mandatory in US but optional in Canada and Europe)
- Hepatitis B surface antigen
- Hepatitis C antibody

10. No late relapse with completely surgically resectable disease. Patients with late relapses (defined as relapse 2 or more years from the date of completion of the last chemotherapy regimen) whose disease is completely surgically resectable are not eligible. Patients with late relapses who have unresectable disease are eligible.

11. No large (2 cm or more) hemorrhagic or symptomatic brain metastases until local treatment has been administered (radiation therapy or surgery). Treatment may begin 7 days or more after completion of local treatment. Patients with small (< 2 cm) and asymptomatic brain metastases are allowed and may be treated with radiation therapy and/or surgery concurrently with Arm A or cycles 1 and 2 of Arm B if deemed medically indicated.

Radiation therapy should not be given concurrently with high-dose carboplatin or etoposide.

12. No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression.
Minimum age
14 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior treatment with high-dose chemotherapy
2. Prior treatment with TIP
*1 cycle of Prior TIP is allowed as bridge to the protocol
3. Prior radiation within 14 days
4. Prior chemotherapy within 16 days (bleomycin within 5 days)
5. Inadequate recovery from prior surgery
6. Concurrent malignancy
7. Large hemorrhagic or symptomatic brain metastases
*Become eligible 7 days or more after local treatment (surgery or RT)
8. Fully resectable late relapse (2 years or more before relapse)
9. Concurrent malignancy

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation). Stratified allocation is employed in the study. Patients are stratified by the following factors:
1. Geographic region (Europe, North America, Australia) that the patient lives in;
and by their
2. Modified IPFSG risk classification: i.e. allocated to one of the 3 groups: (i) low, (ii) intermediate and (iii) high.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The study is an international collaboration with Europeans sites. It is anticipated that 168
patients from the Alliance sites and 252 patients from the European sites will be enrolled on the trial. These numbers are approximate and each region will continue to enroll patients even if the target number per site has not been reached.

It is expected that a proportion of patients will be cured. The Berkson-Gage exponential cure rate model is used to design this trial. This model assumes that a proportion of patients (p) will be cured and (1-p) who will fail according to an exponential distribution with rate 'lambda'.

The overall survival function S(t) for the TIP (arm A) and TI-CE (arm B) are expressed as:
S1(t) = p+ (1-p)exp(-'lambda't)
S2 (t) = (p+ (1-p)exp(-'lambda't))'theta'

Respectively, where 'theta' is the hazard ratio under the proportional hazards alternative. It is assumed that 35% of patients will be cured and the median survival time for patients
randomized to TIP who are not cured to be 1.5 years. Moreover, it is hypothesized that TICE
will reduce the hazard by 29% under that proportional hazards alternative ('theta' =0.71). The
expected information in both arms is 232 deaths. The calculation assumes a yearly
enrollment rate of 72 patients accrued over 5.8 years and a post-accrual period of 4.5 years
after study closure. This design has 81% power assuming a one sided type I error rate of
0.05.

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)
NSW,QLD,VIC
Recruitment hospital [1] 11058 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [2] 11059 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 11060 0
Box Hill Hospital - Box Hill
Recruitment hospital [4] 11061 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 22860 0
2050 - Camperdown
Recruitment postcode(s) [2] 22861 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 22862 0
3128 - Box Hill
Recruitment postcode(s) [4] 22863 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 10516 0
United States of America
State/province [1] 10516 0
Country [2] 10517 0
Belgium
State/province [2] 10517 0
Country [3] 10518 0
Denmark
State/province [3] 10518 0
Country [4] 10519 0
France
State/province [4] 10519 0
Country [5] 10520 0
Ireland
State/province [5] 10520 0
Country [6] 10521 0
Italy
State/province [6] 10521 0
Country [7] 10522 0
Netherlands
State/province [7] 10522 0
Country [8] 10523 0
Spain
State/province [8] 10523 0
Country [9] 10524 0
Switzerland
State/province [9] 10524 0
Country [10] 10525 0
United Kingdom
State/province [10] 10525 0
Country [11] 10527 0
Germany
State/province [11] 10527 0

Funding & Sponsors
Funding source category [1] 299653 0
Other Collaborative groups
Name [1] 299653 0
Australian and New Zealand Urogenital and Prostate Cancer Trials (ANZUP)
Address [1] 299653 0
119/143 Missenden Rd, Camperdown NSW 2050
Country [1] 299653 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Alliance for Clinical Trials in Oncology
Address
221 Longwood Avenue, Room 108, Boston, MA 02115
Country
United States of America
Secondary sponsor category [1] 298985 0
Other Collaborative groups
Name [1] 298985 0
Australian and New Zealand Urogenital and Prostate Cancer Trials (ANZUP)
Address [1] 298985 0
119/143 Missenden Rd, Camperdown NSW 2050
Country [1] 298985 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300551 0
Sydney Local Health District, Royal Prince Alfred Research Ethics and Governance
Ethics committee address [1] 300551 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 300551 0
Australia
Date submitted for ethics approval [1] 300551 0
23/01/2018
Approval date [1] 300551 0
02/03/2018
Ethics approval number [1] 300551 0
HREC/18/RPAH/11

Summary
Brief summary
The purpose of this study is to determined how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplants in patients with germ cell tumours.

Who is it for?

You may be eligible for this study if you are 14 years and older and have a germ cell tumour that have either improved or not responded to treatment.

Study details

Participants will be randomised to one of two treatments:
1. Standard dose chemotherapy: included 4 cycles of chemotherapy every 21 days (including paclitaxel, ifosfamide, cisplatin and pegylated G-CSF).
2. High dose chemotherapy and stem cell transplants: including 2 cycles of chemotherapy (including paclitaxel, ifosfamide and pegylated G-CSF) and 3 cycles of chemotherapy (including carboplantin, etoposide and pegylated G-CSF) plus stem cell therapy.

Drugs used in chemotherapy such as those used in this study work in different ways to stop the growth of tumour cells, either by killing the cells, by stopping them from dividing or by stopping them spreading. Those in the high dose group will also be receiving stem cell transplants which should replace the blood-forming cells destroyed in chemotherapy.

Blood tests and other physical examinations will be conducted throughout the trial.

It is hoped that this research will determine whether high dose combination chemotherapy and stem cell transplants are more effective than standard dose combination chemotherapy in patients with refractory or relapsed germ cell tumours.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84034 0
A/Prof Peter Grimison
Address 84034 0
NHMRC Clinical Trials Centre
The University of Sydney
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050
Country 84034 0
Australia
Phone 84034 0
+61 2 9562 5000
Fax 84034 0
+61 2 9562 5094
Email 84034 0
tiger@ctc.usyd.edu.au
Contact person for public queries
Name 84035 0
Ms TIGER Trial Coordinator
Address 84035 0
NHMRC Clinical Trials Centre
The University of Sydney
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050
Country 84035 0
Australia
Phone 84035 0
+61 2 9562 5000
Fax 84035 0
+61 2 9562 5094
Email 84035 0
tiger@ctc.usyd.edu.au
Contact person for scientific queries
Name 84036 0
A/Prof Peter Grimison
Address 84036 0
NHMRC Clinical Trials Centre
The University of Sydney
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050

Country 84036 0
Australia
Phone 84036 0
+61 2 9562 5000
Fax 84036 0
+61 2 9562 5094
Email 84036 0
tiger@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This has not been discussed as to something that will be available for the trial.
What supporting documents are/will be available?
No other documents available
Summary results
No Results