NCT03726281

Nivolumab in Platinum Recurrent or Refractory Metastatic Germ Cell Tumors

Phase II Multi-institutional Proof of Concept Single-arm Trial of Nivolumab in the Treatment of Patients With Platinum Recurrent or Refractory Metastatic Germ Cell Tumors

• Status: Withdrawn
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: Hospital Beatriz Ângelo · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

To assess the clinical activity of nivolumab monotherapy, as measured by the investigator-assessed clinical benefit rate (CBR), in patients with platinum-recurrent or platinum-refractory metastatic germ cell tumors (GCT). CBR is defined by sum of complete responses (CR), partial responses (PR) and stable disease (SD) for at least 3 months, with stable or declining tumor markers (αFP and HCG), using Response Evaluation Criteria In Solid Tumors (RECIST 1.1).

Detailed description

For patients with testicular GCT, there is no consensus on the most effective treatment for men who relapse after first-line chemotherapy for advanced disease, between salvage conventional cisplatin-based dose chemotherapy and high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell rescue (ASCT). A significant number of patients with recurrent metastatic testicular GCT can still be cured with salvage chemotherapy but long term survival becomes negligible for cisplatin-refractory disease or for patients beyond second relapse. HDCT with ASCT should be considered for patients with recurrent metastatic disease, at least beyond second relapse, although its therapeutic impact has not yet been proven in randomized controlled trials. In contrast, patients with platinum-refractory metastatic GCT and those with recurrent primary mediastinal nonseminomatous GCT (PMNSGCT) are rarely cured by conventional dose salvage chemotherapy. Immunotherapy with anti-PD-1 and anti-PD-L1 antibodies have demonstrated clinical activity in multiple malignancies, with durable remissions and long-term survivors in patients with metastatic malignant melanoma, non-small cell lung cancer and renal cell cancer, and are being studied in several other tumor types. In GCT a recent study identified PD-L1 expression in 73% of all seminomas and in 64% of all non-seminomas. Patients with low PD-L1 expression had significantly better progression-free survival (PFS) and OS compared to patients with high PD-L1 expression. Frequent expression of PD-L1 in testicular GCT suggests that these patients may benefit from checkpoint inhibitor treatment with anti-PD-1 or anti-PD-L1 antibodies. So far there are only case reports of nine patients with GCT treated with immune check-point inhibitors. One patient, initially diagnosed with metastatic melanoma but subsequently reclassified as non-seminomatous GCT, was treated with a single dose of nivolumab and experienced clinical resolution of lymphadenopathy, decrease in serum tumor markers and a 47% tumor burden reduction by immune-related response criteria. Another report includes seven patients treated with checkpoint inhibitors (nivolumab or pembrolizumab) as a compassionate use off-label treatment attempt for highly-pretreated GCT. Four patients died shortly after beginning treatment due to tumour progression, the remaining three patients received treatment for at least 6 months and long-term tumor response was achieved in two of the three, both of them with tumors highly positive for PD-L1 staining. Another case report was published of a man with a poor-risk nonseminomatous GCT who had disease progression after HDTC/ASCT and had a durable response to immune checkpoint inhibitor. Recently a single arm phase II trial of pembrolizumab in patients with incurable platinum refractory GCT was presented at ASCO Annual Meeting 2017. This was the first reported trial evaluating immune checkpoint inhibitors in GCT, enrolling 12 male patients age ≥ 18 with metastatic GCT that had progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (CDCT or HDCT). All patients had non-seminoma, the primary tumor site was testis in 11 patients and mediastinum in 1 patient. 5 patients had late relapse (\> 2 years) and 6 patients had received prior HDCT. No partial or complete responses were observed, 2 patients achieved radiographic stable disease for 12 and 9 weeks but with continuing rise of AFP, suggesting that Pembrolizumab has no clinically meaningful activity in refractory GCT. Thus, with limited and conflicting data, further studies with immune checkpoint inhibitors in patients with recurrent metastatic GCT are required.

Conditions

• Germ Cell Tumors

Interventions

Type	Name	Description
DRUG	Nivolumab	Nivolumab 240 mg, IV

Timeline

• Start date: 2018-10-01
• Primary completion: 2019-06-30
• Completion: 2019-06-30
• First posted: 2018-10-31
• Last updated: 2019-08-21

Locations

1 site across 1 country: Portugal

Regulatory

• FDA-regulated drug study