Neoplasms

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Neoplasms, Germ Cell and Embryonal

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Pregnancy Complications, Neoplastic

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Female Urogenital Diseases

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Germ Cells Tumors

Central Nervous System Germinoma

Testicular Seminoma

Nonseminomatous Germ Cell Tumor

Malignant Germ Cell Tumor

Testicular Yolk Sac Tumor

Antineoplastic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Anti-Allergic Agents

Central Nervous System Depressants

Dermatologic Agents

Etoposide

Paclitaxel

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Albumin-Bound Paclitaxel

Cisplatin

Ifosfamide

Dexamethasone acetate

Etoposide phosphate

Diphenhydramine

Promethazine

Histamine H2 Antagonists

Isophosphamide mustard

Mesna

Lenograstim

Tubulin Modulators

Antimitotic Agents

Enzyme Inhibitors

Adjuvants, Immunologic

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients will receive treatment for 4 cycles administered every 21 days.

Cycles 1-4 (1 cycle = 21 days)

* paclitaxel 250 mg/m\^2 IV over 24 hours on Day 1 including premedication as defined in the protocol (eg, dexamethasone, diphenhydramine and H2 blocker)
* ifosfamide 1500 mg/m\^2 IV daily on Days 2-5 with mesna protection as defined in the protocol
* cisplatin 25 mg/m\^2 IV daily on Days 2-5
* pegylated G-CSF 6 mg subcutaneous on Day 6 or 7 or G-CSF as defined in the protocol on Days 6-18

Patients may commence with each Arm A cycle provided they meet the criteria as defined in the protocol.

Patients will receive treatment for a total of 5 cycles.

Cycles 1-2 (1 cycle = 14 days)

* paclitaxel 200 mg/m\^2 IV over 3 hours on Day 1 including premedication as defined in the protocol (eg, dexamethasone, diphenhydramine and H2 blocker)
* ifosfamide 2000 mg/m\^2 IV daily on Days 1-3 with mesna protection as defined in the protocol
* G-CSF 10 µg/kg subcutaneously 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)
* leukapheresis every 14 days, if there is an inadequate number of CD34+ cells/kg collected in cycle 1

Cycles 3-5 (1 cycle = 21 days)

* carboplatin daily on Days 1-3
* etoposide 400 mg/m\^2 daily on Days 1-3
* stem cell reinfusion on day 5
* pegylated G-CSF 6 mg subcutaneously or G-CSF at approximately 5 µg/kg daily on Days 5-15

Patients may commence with each Arm B cycle provided they meet the criteria as defined in the protocol.

paclitaxel

ifosfamide

cisplatin

pegylated G-CSF

G-CSF

carboplatin

etoposide phosphate

stem cell reinfusion

Darren Feldman, MD

This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.

The study is an international collaboration with European sites. Collaborators on the study include the National Cancer Institute, the European Organization for Research and Treatment of Cancer and the Movember Foundation. Randomization will be stratified by region (North America and Europe) and by modified IPFSG (International Prognostic Factor Study Group) risk classification (low, intermediate and high). The primary and secondary objectives are described below.

Primary Objective:

1. To compare the overall survival in patients treated with conventional-dose chemotherapy using the TIP regimen with high-dose chemotherapy (HDCT) plus autologous stem cell transplant (ASCT) using the TI-CE regimen as initial salvage treatment of patients with relapsed or refractory germ cell tumors (GCT)

Secondary Objectives:

1. To compare the progression-free survival (PFS) of patients treated with initial salvage HDCT with TI-CE versus initial salvage CDCT with TIP
2. To compare the favorable response rate (FRR) of patients treated with initial salvage HDCT with TI-CE versus initial salvage CDCT with TIP
3. To compare the toxicity, including treatment-related mortality, associated with high-dose chemotherapy and ASCT using TI-CE compared with conventional-dose chemotherapy using TIP as initial salvage treatment for patients with relapsed or refractory GCT
4. 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, randomization will be stratified by a modification of their 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).
5. To evaluate the association between tumor marker decline rates of Alpha-Fetoprotein (AFP) and Human Chorionic Gonadotropin (HCG) with OS and PFS.

Treatment is to continue until disease progression, unacceptable toxicity or completion of all protocol treatment.

Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors

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

National Cancer Institute (NCI)

European Organisation for Research and Treatment of Cancer - EORTC

Movember Foundation

Institute of Cancer Research (ICR), United Kingdom

Cancer Research UK

UNICANCER

Irish Group CTI

Alliance for Clinical Trials in Oncology

In arm patients receive a TI-CE regime based on paclitaxel and ifosfamide in cycles 1-2 and carboplatin and etoposide in cycles 3-5.

TI: Paclitaxel 200mg/m² on day 1, Ifosfamide 2000mg/m² daily from days 1 to 3 of 14-day cycle. G-CSF 10 micrograms/Kg SC daily day on days 6-14 day or until CD34 harvest. Leukapheresis will be performed starting on day 11 in case blood level of CD45+CD34+ above 20x10\^6/L is achieved.

CE: Carboplatin AUC=8 IV daily days -4 to -2, Etoposide 400mg/m\^2 IV daily days -4 to -2, autlologous stemm cell transplantation \>=2\*10\^6/Kg at day 0, GCSF support from day 4 until the recovery of neutrophils above 1\*10\^9/L.

Patients will receive two cycles of TI followed by 3 cycles of CE in case at least 6\*10\^6 CD34+ stem cells will be harvested.

High-dose chemotherapy (TI- 2 cycles, CE- 3 cycles )

Anna Semenova, MD, PhD

Anna I Semenova, MD, PhD

Aleksei M Belyaev, MD,DSc,Prof.

Tatyana Yu Semiglazova, MD,DSc,Prof.

This is a prospective, single-center, non-randomized phase II study. Patients with germ cell tumors of gonadal and extragonadal localization who have progressed after prior platinum-containing first-line chemotherapy will receive high-dose chemotherapy with TI (2 cycles) folollowed by high dose CE chemotherapy with autologous stem cell transplantation (3 cycles). The primary endpoint of the study is to evaluate the efficacy high-dose chemotherapy as second-line drug therapy for patients with advanced germ cell tumors.

Germ cell tumors are curable diseases. Only a small proportion of patients fail to be cured: those who experience a primary resistance to chemotherapy and those who relapsed after first line conventional dose cisplatin-based chemotherapy. Nowadays, there is heterogeneity of practice in salvage approaches. This includes conventional chemotherapy high dose chemotherapy with autologous stem cell transplant. Best choice of the therapy strategy is an unmet clinical need now. This is why this single-center, non-randomized phase II study will be conducted at the N.N. Petrov National Medical Research Center of Oncology. Patients with germ cell tumors of gonadal and extragonadal localization who have progressed after prior platinum-containing first-line chemotherapy will receive two cycles of high-dose TI (Paclitaxel 200mg/m² on day 1, Ifosfamide 2000mg/m² daily from days 1 to 3 of 14-day cycle. G-CSF 10 micrograms/Kg SC daily day on days 6-14 day or until CD34 harvest; leukapheresis will be performed starting on day 11 in case of CD45+CD34+ blood level above 20x10\^6/L is achieved), followed by three cycles of high dose CE (Carboplatin AUC=8 IV daily days -4 to -2, Etoposide 400mg/m\^2 IV daily days -4 to -2, autlologous stem cell transplantation at day 0, GCSF support from day 4.) The primary endpoint of the study is to evaluate the efficacy by measuring progression-free survival. The secondary endpoints of the trial are overall survival, response rate by RECIST, safety and prognostic factors analysis.

High-dose Chemotherapy as Second-line Drug Therapy for Relapsed Germ Cell Tumors

All toxicities will be evaluated and recorded based on the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Evaluation of the efficacy of high-dose TI (2 cycles)-CE (3 cycles) chemotherapy in patients with germ cell tumors of gonadal and extragonadal localization who progressed after prior platinum-containing first-line chemotherapy and received high-dose TI (2 cycles)-CE (3 cycles) chemotherapy, depending on the prognosis group (IGCCCG classification (1997), IGCCCG Update Model (2021)).

European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact. The EORTC QLQ-C30 GHS/QoL score ranges from 0 to 100; High score indicates better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL.

Evaluation of the impact of patient nutritional support and the relationship between patient nutrition and the incidence of non-hematologic complications (mucositis, colitis, infectious complications)

In case of poor mobilization according to the criteria of the European Society of Bone Marrow Transplantation, the addition of Plerixafor at a dose of 24 mg to the mobilization is envisaged.

An evaluation of the feasibility of improving mobilization rates with Plerixafor is planned.

Incidence of complete, partial response, stable and progressive disease by RECIST 1.1 system

N.N. Petrov National Medical Research Center of Oncology

clinical oncologist

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors	NCT02375204	Germ Cell Tumor Teratoma Choriocarcinoma Germinoma Mixed Germ Cell... Yolk Sac Tumor Childhood Terat... Malignant Germ ... Extragonadal Se... Non-seminomatou... Seminoma	paclitaxel ifosfamide cisplatin pegylated G-CSF G-CSF carboplatin etoposide phosp... stem cell reinf...	14 Years -	Alliance for Clinical Trials in Oncology
High-dose Chemotherapy as Second-line Drug Therapy for Relapsed Germ Cell Tumors	NCT06418789	Germ Cell Tumor	High-dose chemo...	18 Years -	N.N. Petrov National Medical Research Center of Oncology
High-dose Chemotherapy as Second-line Drug Therapy for Relapsed Germ Cell Tumors	NCT06418789	Germ Cell Tumor	High-dose chemo...	18 Years -	N.N. Petrov National Medical Research Center of Oncology
Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors	NCT02375204	Germ Cell Tumor Teratoma Choriocarcinoma Germinoma Mixed Germ Cell... Yolk Sac Tumor Childhood Terat... Malignant Germ ... Extragonadal Se... Non-seminomatou... Seminoma	paclitaxel ifosfamide cisplatin pegylated G-CSF G-CSF carboplatin etoposide phosp... stem cell reinf...	14 Years -	Alliance for Clinical Trials in Oncology
Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors	NCT02375204	Germ Cell Tumor Teratoma Choriocarcinoma Germinoma Mixed Germ Cell... Yolk Sac Tumor Childhood Terat... Malignant Germ ... Extragonadal Se... Non-seminomatou... Seminoma	paclitaxel ifosfamide cisplatin pegylated G-CSF G-CSF carboplatin etoposide phosp... stem cell reinf...	14 Years -	Alliance for Clinical Trials in Oncology

Spots Global Cancer Trial Database for malignant germ cell neoplasm