Avelumab in Refractory Testicular Germ Cell Cancer.

NCT ID: NCT03403777

Last Updated: 2019-03-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-15
• Study Completion Date: 2019-02-28

Brief Summary

This is a proof-of-concept study to define efficacy of AVELUMAB in patients with multiple relapsed/refractory germ cell tumors (GCTs). Data suggest that PD-L1 is overexpressed in TGCTs, and PD-L1 expression is significantly higher in GCTs in comparison to normal testicular tissue.Patients with low PD-L1 expression had significantly better progression-free survival (hazard ratio [HR] = 0.40, 95% CI (0.16 - 1.01, p = 0.008) and overall survival (HR = 0.43, 95% CI (0.15 - 1.23, p = 0.040) compared to patients with high PD-L1 expression. These data suggest that PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs and that there is strong rationale to inhibit PD-1/PD-L1 signaling in GCTs.

Detailed Description

Germ-cell tumours (GCTs) are extraordinarily chemosensitive and resemble the clinical and biological characteristics of a model for the cure of cancer. Nonetheless, a small proportion of patients do not have a durable complete remission (CR) with initial chemotherapy. Only 20-40% of them will be cured with the use of platinum-containing standard-dose or high-dose salvage chemotherapy with autologous stem cell transplantation (ASCT). Patients who fail to be cured after second-line salvage therapy have an extremely poor prognosis and long term survival had been documented in <5%. Paclitaxel plus ifosfamide and cisplatin is considered as a standard salvage chemotherapy in relapsed good prognosis GCTs, however, up to 40% of favourable prognosis patients failed to achieve durable response to this combination, and therefore new treatment strategies are warranted.

Recent data suggest that PD-L1 is overexpressed in TGCTs, including 73% seminomas and 64% non-seminomatous tumors, but none of normal testicular tissue specimens exhibited PD-L1 expression. In previous study that included 140 patients, PD-L1 was significantly higher in GCTs in comparison to normal testicular tissue (mean QS = 5.29 vs. 0.32, p < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features including ≥ 3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival (hazard ratio [HR] = 0.40, 95% CI (0.16 - 1.01, p = 0.008) and overall survival (HR = 0.43, 95% CI (0.15 - 1.23, p = 0.040) compared to patients with high PD-L1 expression (Figure 1).

These data suggest that PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs and that there is strong rationale to inhibit PD-1/PD-L1 signaling in GCTs and phase II study is warranted.

Conditions

Testicular Neoplasms; Neoplasms, Germ Cell and Embryonal; Neoplasms; Testicular Diseases; Gonadal Disorders; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Avelumab

AVELUMAB will be administered intravenously 10mg/kg every 2 weeks. Courses will be repeated every 14 days until progression or unacceptable toxicity. AVELUMAB will be administered as a 1-hour (-10 minutes / +20 minutes, i.e., 50-80 minutes) intravenous (i.v.) infusion. The dose of AVELUMAB will be calculated based on the weight of the subject determined on the day prior to or the day of each drug administration.

Group Type: EXPERIMENTAL

Avelumab

Intervention Type: DRUG

AVELUMAB will be administered intravenously 10mg/kg every 2 weeks.

Interventions

Avelumab

AVELUMAB will be administered intravenously 10mg/kg every 2 weeks.

Intervention Type: DRUG

Other Intervention Names

Bavencio

Eligibility Criteria

Inclusion Criteria

1. Signed written informed consent

2. Men aged 18 years or older

3. ECOG performance status: 0-1

4. Histologically confirmed extracranial primary germ cell cancer, seminoma, or nonseminoma

5. Rising serum markers (i.e., alpha-fetoprotein and human chorionic gonadotropin) on sequential measurement or biopsy-proven unresectable germ cell cancer

6. Refractory GCTs e.g. patients relapsing after high-dose chemotherapy or for patients non fit enough for high-dose chemotherapy

7. Primary mediastinal GCTs in first relapse

8. Patient's disease must not be amenable to cure with either surgery or chemotherapy in the opinion of investigator,

9. RECIST 1.1 Measurable disease

10. Adequate hematologic function defined by ANC ≥ 1500/mm3, platelet count ≥ 100 000/mm3 and hemoglobin level ≥ 9g/dl.

11. Adequate liver function defined by a total bilirubin level ≤ 1.5 ULN, and ALT, AST ≤ 2.5 × ULN . or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to the liver).

12. Adequate renal function: measured or calculated (by Cockcroft formula) creatinine clearance ≥ 30 ml/min. Cockcroft formula: CLcr = [(140-age) x weight(Kg)]/[72 x creat (mg/dl)]

13. At least 4 weeks must have elapsed since the last radiotherapy and/or chemotherapy before study entry,

14. At least 4 weeks must have elapsed since the last major surgery

15. Complete recovery from prior surgery, and/or reduction of all adverse events from previous systemic therapy or radiotherapy to grade 1,

16. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

17. Highly effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use 2 highly effective contraception, defined as methods with a failure rate of less than 1 % per year. Highly effective contraception is required at least 28 days prior, throughout and for at least 30 days after avelumab treatment.

2. Other prior malignancy except successfully treated non-melanoma skin cancer

3. No prior PD-1/PD-L1 inhibitor

4. Other concurrent approved or investigational anticancer treatment, including surgery, radiotherapy, chemotherapy, biologic-response modifiers, hormone therapy, or immunotherapy

5. Female patients

6. Patients infected by the Human Immunodeficiency Virus (HIV)

7. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.

8. Other significant diseases: e.g. immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; Patients with other severe acute or chronic medical condition, or laboratory abnormality that would impair, in the judgment of investigator, excess risk associated with the study participation, study treatment administration, or may interfere with the interpretation of study results and, which, in judgment of the investigator, would make the patient inappropriate for entry into this study.

9. Hypersensitivity to any compound of the drug

10. Sexually active men not using highly effective birth control if their partners are women of child-bearing potential

11. All subjects with brain metastases, except those meeting the following criteria:

• Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment
• No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
• Subjects must be either off steroids or on a stable or decreasing dose of <10mg daily prednisone (or equivalent)

12. Prior organ transplantation, including allogeneic stem cell transplantation

13. Significant acute or chronic infections including, among others:

14. Active infection requiring systemic therapy

• Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive)

15. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:

1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible

2. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day

3. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation...) are acceptable

4. steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication).

16. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)

17. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable

18. Known alcohol or drug abuse

19. All other significant diseases (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment

20. Any psychiatric condition that would prohibit the understanding or rendering of informed consent

21. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: collaborator

National Cancer Institute, Slovakia

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michal Mego, prof

Role: STUDY_CHAIR

National Cancer Institute (NCI)

Locations

National Cancer Institute

Bratislava, , Slovakia

Countries

Slovakia

References

1) Broun ER et al. Ann Intern Med 1993; 117: 124-8 2) Cierna et al., Ann Oncol, Ann Oncol. 2016 Feb;27(2):300-5. 3) Feldman et al Cancer 2012;118:981-6. 4) Horwich A, et al. Lancet 2006; 367: 754-65 5) Kollmannsberger C et al. Cancer 2006; 106: 1217-26 6) Kondagunta GV et al. J Clin Oncol. 2005 23:6549-55. 7) Mardiak J et al. Neoplasma, 2005; 52: 497-501 8) Fankhauser, C. D et al. Br J Cancer. 2015, 113: 411-413 9) Heery et al. J Clin Oncol 33, 2015 (suppl; abstr 3055) 10) Yamada et al. J Clin Oncol 33, 2015 (suppl; abstr 4047) 11) Disis et al. J Clin Oncol 33, 2015 (suppl; abstr 5509) 12) Gulley et al. J Clin Oncol 33, 2015 (suppl; abstr 8034) 13) Shitara K et al. J Clin Oncol 33, 2015 (suppl; abstr 3023) 14) Kelly K et al. J Clin Oncol 33, 2015 (suppl; abstr 3044) 15) Boyerinas B et al. Cancer Immunol Res. 2015 Oct;3(10):1148-57.

Reference Type: BACKGROUND

Other Identifiers

NCISlovakia

Identifier Type: -

Identifier Source: org_study_id