Brentuximab Vedotin (SGN-35) as Salvage Treatment for CD30-positive Germ Cell Tumors

Brentuximab Vedotin (SGN-35) as Salvage Therapy for Males With Advanced and Platinum-resistant Germ-cell Tumors. An Open Label, Single Group, Phase 2 Trial.

The purpose of the study is to assess the activity of Brentuximab vedotin in refractory germ cell tumors.

Study Overview

• Status: Completed
• Conditions: Germ Cell Cancer
• Intervention / Treatment: Drug: Brentuximab Vedotin

Detailed Description

Complete responses with third-line or later salvage chemotherapy (CT) for germ cell tumors (GCT) range 0% to 10% and are usually short-lived and nearly all patients (pts) progressing after multiple courses or high-dose CT will ultimately die from progressive disease.

Cluster of Differentiation antigen-30 (CD30) is expressed by untreated embryonal carcinoma (ECA) thus lending support to a rationale for a targeted approach. The investigators retrospectively re-assessed ECA to strongly retain CD30 staining in most cases (>70%), even after multiple courses or high-dose CT. Moreover, a negative prognostic value of CD30 expression by residuals after CT, particularly in the salvage setting, was set. Brentuximab vedotin is an antibody-drug conjugate consisting of the chimeric anti-CD30 antibody chemically conjugated to an antitubulin synthetic analog (MMAE).

Proof of activity will provide rationale for developing first-line chemo-immunotherapy or maintenance immunotherapy for selected high-risk pts. The primary objective of the study will be the activity of Brentuximab vedotin in refractory GCT. Secondary objectives will include safety and survival.

24 pts with biopsy-proven CD30 positive GCT will receive intravenous Brentuximab vedotin at the dose of 1.8 mg/Kg every 3 weeks until disease progression or onset of unacceptable toxicity. Further eligibility requirements will include failure of 2 or 3 platinum-based CT (prior high-dose CT is allowed). All pts will undergo measurement of serum tumor markers, a computed tomography and a positron emission tomography (PET) scan every weeks. An optimal Simon's 2-stage design will be applied. The primary endpoint is the objective response-rate (ORR). An ORR of 5% is not promising, while a 25% rate will be promising. In stage 1, 9 evaluable patients will be accrued. The type I and II error are both set at 10%.

Additional post-treatment tissue will be available for pts undergoing surgery in the treatment time-course. Tissue array blocks will be constructed from samples of all pts. Assessment will include mutational analysis of most-frequently mutated genes. Two serum aliquots will be collected at baseline and during/end of treatment to assess circulating CD30.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Mi
    • Milano, Mi, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei Tumori

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Age of at least 18 years.
• Confirmation of germ cell tumor histology based on pathologic review at the study site.
• Presence of a CD30 positive embryonal carcinoma component.
• Unequivocal progression of measurable disease.
• A minimum of 2 and a maximum of 3 platinum-based chemotherapy lines for metastatic disease EXCEPT for primary mediastinal germ cell tumors where failure of first-line chemotherapy only is accepted.
• Prior high dose chemotherapy with hematopoietic stem cell rescue is allowed.

Exclusion Criteria:

• Failure to meet any of the above inclusion criteria.
• Patients with late-relapse (defined as relapse occurring after at least 2 years from the date of completion of the last chemotherapy regimen) whose disease is completely surgically resectable (and for whom initial surgical extirpation is recommended) are ineligible. Patients with unresectable late disease relapse are eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brentuximab Vedotin; Intravenous Brentuximab Vedotin at the dose of 1.8 mg/Kg every 3 weeks until disease progression or onset of unacceptable toxicity	Drug: Brentuximab Vedotin; Intravenous Brentuximab Vedotin at the dose of 1.8 mg/Kg every 3 weeks until disease progression or onset of unacceptable toxicity; Other Names: Adcetris; SGN-35

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The number of objective responses (partial and complete responses) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 integrated with response of serum tumor markers.	Six weeks after the first administration of the study drug.

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-Free Survival	3 months after the initiation of study treatment
Overall Survival	Six months after the initiation of study treatment
Incidence of adverse events related to the study drug	Six weeks after the initiation of the study drug and every 6 weeks thereafter up to 16 weeks.

Other Outcome Measures

Outcome Measure	Time Frame
Metabolic response to Brentuximab Vedotin measured by means of a Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) scan.	Six weeks after the first administration of the study drug.

Collaborators and Investigators

• Sponsor: Fondazione Michelangelo
• Collaborators: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Millennium Pharmaceuticals, Inc.
• Investigators: Study Chair: Alessandro M Gianni, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Study Chair: Roberto Salvioni, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Principal Investigator: Andrea Necchi, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan

Publications and helpful links

Helpful Links

• Web site of the study Sponsor

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2013
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): September 1, 2017

Study Registration Dates

• First Submitted: April 20, 2013
• First Submitted That Met QC Criteria: May 8, 2013
• First Posted (Estimate): May 10, 2013

Study Record Updates

• Last Update Posted (Actual): February 7, 2018
• Last Update Submitted That Met QC Criteria: February 6, 2018
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Metastatic; Brentuximab Vedotin; Testicular neoplasms; Germ Cell cancers; Embryonal Carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Germ Cell and Embryonal; Antineoplastic Agents; Antineoplastic Agents, Immunological; Brentuximab Vedotin
• Other Study ID Numbers: FM-12-GCT01; 2012-004508-36 (EudraCT Number)