Nivolumab in Platinum Recurrent or Refractory Metastatic Germ Cell Tumors

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Brief Title

Nivolumab in Platinum Recurrent or Refractory Metastatic Germ Cell Tumors

Official Title

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

Brief 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Clinical Benefit Rate (CBR, %)

Secondary Outcome

 CR + marker-negative PR (%)

Condition

Germ Cell Tumors

Intervention

Nivolumab

Study Arms / Comparison Groups

 single-arm trial of Nivolumab
Description:  Multi-institutional, single arm phase II trial with Simon's optimal two-stage design, to evaluate the clinical benefit of Nivolumab monotherapy in patients with platinum-recurrent or platinum-refractory metastatic GCT. No randomization or blinding is involved.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

0

Start Date

October 1, 2018

Completion Date

June 30, 2019

Primary Completion Date

June 30, 2019

Eligibility Criteria

        Inclusion Criteria:

          -  Signed Informed Consent

          -  Male or female, aged 18 years

          -  Metastatic GCT, seminoma or non-seminoma, previously treated with standard doublet or
             triplet cisplatin-containing chemotherapy for metastatic disease in: a) second or
             further relapse from primary testicular, retroperitoneal or ovarian GCT; b) first or
             further relapse of PMNSGCT; c) primary-refractory GCT (defined as progression within 8
             weeks of finishing first-line chemotherapy for advanced GCT); or d) "late relapse" (>
             2 years after cisplatinum-containing chemotherapy for metastatic GCT) that is not
             amenable to surgical resection.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2.

          -  Evidence of recurrent disease by imaging (CT or MR) or rising tumor markers (αFP or
             HCG). NOTE: If a rising tumor marker is the only evidence of progressive disease, at
             least 2 consecutive rising values at least one week apart are needed and alternative
             causes of increased serum levels of these markers must be excluded (cross reaction
             with luteinizing hormone (LH) (that can be tested if needed by testosterone
             suppression of LH), liver disease, use of marijuana, or second primary tumor)

          -  Received initial cisplatin based combination therapy, such as BEP, EP, VIP, or similar
             regimens AND, for primary testicular or ovarian GCT, progression after at least one
             'salvage' chemotherapy regimen (such as, TIP, VeIP, VIP or high dose chemotherapy with
             ASCT).

          -  "Failure" of prior therapy is defined as: a >20% increase in the sum of the longest
             diameter of target lesions during prior therapy which is not amenable to surgical
             resection; the presence of new tumor lesions that are not amenable to surgical
             resection; an increase in αFP or HCG (two separate determinations at least one week
             apart are required if rising tumor markers are the only evidence of treatment failure)
             in patients with metastatic disease. NOTE: Patients with clinically growing "teratoma"
             (normal or declining tumor markers and radiographic progression) should be considered
             for surgery.

          -  Use an adequate method of contraception starting with the first dose of study therapy
             through 5 months after the last dose of study therapy.

          -  Measurable disease according to RECIST v1.1 obtained by imaging within 28 days prior
             to registration.

          -  Non-measurable but evaluable disease associated increasing tumor markers (αFP and HCG)
             may be eligible, upon review by two PIs.

        Exclusion Criteria:

          -  Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or
             any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
             pathways.

          -  History of allergy or hypersensitivity to study drug components.

          -  Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
             may increase the risk associated with study participation or study drug
             administration, impair the ability of the patient to receive protocol therapy, or
             interfere with the interpretation of study results.

          -  Patients with an active, known or suspected autoimmune disease.

          -  Participants with type I diabetes mellitus, hypothyroidism only requiring hormone
             replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger are permitted to enrol.

          -  Patients with a condition requiring systemic treatment with either corticosteroids
             (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of study drug administration. Inhaled or topical steroids and adrenal replacement
             steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of
             active autoimmune disease.

          -  Diagnosis of immunodeficiency or current treatment with systemic steroid therapy or
             any other form of immunosuppressive therapy within 7 days prior to the first dose of
             trial treatment.

          -  Known history of active Tuberculosis, Human Immunodeficiency Virus (HIV) or active
             Hepatitis B (i.e. HBsAg reactive) or Hepatitis C (i.e. HCV RNA [qualitative] is
             detected).

          -  Treatment with a live vaccine within 30 days of planned start of study therapy. NOTE:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (i.e. Flu-Mist®) are live
             attenuated vaccines, and are not allowed.

          -  Treatment with chemotherapy, targeted small molecule therapy or radiation therapy
             within 3 weeks prior to study Day 1 or without recovery (ie. ≤ Grade 1) from AEs from
             such previously administered agents. Patients with alopecia and ≤ Grade 2 neuropathy
             are an exception to this criterion and qualify for the study.

          -  Patients with recent major surgery in the previous 14 days prior to starting therapy
             must have recovered adequately from the toxicity and/or complications from the
             intervention.

          -  Prior malignancy active within the previous 3 years except for locally curable cancers
             that have been apparently cured, such as basal or squamous cell skin cancer,
             superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

          -  Active central nervous system (CNS) metastases and/or carcinomatous meningitis, other
             than previously treated brain metastases who are stable (without evidence of
             progression by imaging for at least four weeks prior to the first dose of trial
             treatment) and must be either off corticosteroids or on a stable or decrease dose ≤10
             mg daily prednisone (or equivalent).

          -  Presence of interstitial lung disease or history of pneumonitis requiring treatment
             with corticosteroids.

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Portugal

Location Countries

Portugal

Administrative Informations


NCT ID

NCT03726281

Organization ID

HBA_001


Responsible Party

Sponsor

Study Sponsor

Hospital Beatriz Ângelo

Collaborators

 Universidade Nova de Lisboa

Study Sponsor

, , 


Verification Date

August 2019