Study of Brentuximab Vedotin And Bevacizumab In Refractory CD-30 Positive Germ Cell Tumors
Condition: Germ Cell Tumor
MeSH terms: Neoplasms, Germ Cell and Embryonal
Intervention: Brentuximab Vedotin; Bevacizumab
Intervention description: Dose level 1: 1.8 mg/kg every 21 days (up to 180 mg) Dose level -1 :1.2 mg/kg every 21 days ( up to 120 mg); 15 mg/kg every 21 days
Intervention MeSH terms: Bevacizumab; Brentuximab Vedotin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GCT

Summary:

      This is a multi-center phase II study of brentuximab vedotin in combination with bevacizumab
      for the treatment of refractory CD-30+ germ cell tumors (GCT) after disease progression on
      imaging and/or tumor marker progression documented by serially rising alpha-fetoprotein (AFP)
      or beta human chorionic gonadotropin (bHCG) measured on at least 2 consecutive visits and
      determined by treating physician to be clinically significant. Patients unable to receive 2nd
      line of platinum-based chemotherapy due to toxicity or refusal would also be eligible.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male, ≥ 18 years of age

          -  Diagnosis of CD-30 positive germ cell tumor. CD30 expression will be tested by
             immunohistochemistry (IHC) in archival or fresh tumor tissue as is routinely done for
             diagnosis.

          -  Disease progression on imaging or tumor marker progression (clinical significance of
             tumor marker progression to be decided per the discretion of treating physician) after
             at least 2 lines of platinum-based chemotherapies unless patient is ineligible for
             further platinum based chemotherapy or refuses 2nd line platinum based chemotherapy
             due to toxicity. For primary mediastinal germ cell tumors, failure of first-line
             chemotherapy will be accepted. Prior high dose chemotherapy with hematopoietic stem
             cell rescue is allowed. Prior treatment with bevacizumab is allowed.

          -  At least 3 weeks should have elapsed since the last treatment (e.g. chemotherapy,
             targeted small molecule therapy, immunotherapy or radiation) and must have recovered
             to grade 1 or better from the acute effects of prior therapy.

          -  Presence of measurable disease according to RECIST 1.1

          -  ECOG performance status 0 or 1

          -  Adequate marrow and organ function within 28 days prior to study registration as
             defined below:

               -  Leukocytes > 3,000/µL

               -  ANC > 1500/µL

               -  Hemoglobin ≥ 9 g/dL, Note: Blood transfusion will be allowed for patients with
                  hemoglobin < 9 g/dl and G-CSF is allowed for neutropenic patients at time of
                  enrollment.

               -  Platelets > 100,000/mm3

               -  Creatinine: ≤3mg/dl OR if serum creatinine > 3 mg/dl, estimated GFR >30
                  mL/min/1.73m2

               -  INR: <1.5 x institutional upper limit of normal OR < 3 if on warfarin or other
                  anticoagulants. There should be no evidence of active bleeding while on
                  anticoagulants.

               -  Total bilirubin: ≤ 2 x institutional upper limit of normal (ULN)

               -  SGOT (AST) or SGPT (ALT): < 3 x institutional upper limit of normal (< 5 x ULN if
                  liver metastases present)

               -  Proteinuria: If patient has proteinuria, it should be <2+ (< 100 mg/dl or per
                  institutional guidelines). If proteinuria is 2+ or greater (≥ 100 mg/dl per
                  institutional guidelines), patients should undergo a 24- hour urine collection
                  and 24 hour urinary protein should be less than < 2 grams.

          -  Sexually active men with partners of women of childbearing potential must agree to
             practice effective methods of contraception during the study and for 6 months after
             the last treatment

          -  Provide voluntary written consent and HIPAA authorization for release of personal
             health information, approved by an Institutional Review Board/Independent Ethics
             Committee (IRB/IEC)

        Exclusion Criteria:

          -  Prior treatment with Brentuximab Vedotin.

          -  Known active brain metastases and or carcinomatous meningitis. Subjects with
             previously treated brain metastases may participate provided brain metastases are
             stable (without evidence of progression by imaging for at least four weeks prior to
             the first dose of trial treatment and any neurologic symptoms have returned to
             baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to study registration. This exception does not
             include carcinomatous meningitis, which is excluded regardless of clinical stability.

          -  History of blood clots, pulmonary embolism, or deep vein thrombosis in previous 6
             months unless controlled by anticoagulant treatment

          -  Known history of HIV

          -  Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected)

          -  Received a live vaccine within 1 week prior to the first dose of study treatment

          -  Has active autoimmune disease that required systemic treatment with use of disease
             modifying agents, corticosteroids or immunosuppressive drugs

          -  Any clinically significant active infection that requires systemic treatment at the
             time of enrollment.

          -  Known allergy to bevacizumab or brentuximab vedotin or any of its excipients

          -  Patients who have congestive heart failure (NYHA Class III or IV), unstable angina,
             sustained ventricular tachycardia, ventricular fibrillation, clinically significant
             bradycardia, advanced heart block or a history of acute myocardial infarction (MI)
             within 6 months of study registration

          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             in previous 6 months

          -  Prior major surgery within the previous 28 days of study registration and/or presence
             of any non-healing wound, fracture, or ulcer.

          -  Use of an investigational agent within the previous 28 days of study registration.

          -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150 mmHg
             and/or diastolic blood pressure (DBP) of ≥ 90mmHg]. Note: Initiation or adjustment of
             antihypertensive medication(s) is permitted prior to study registration

          -  Arterial thromboembolic events, including transient ischemic attack (TIA),
             cerebrovascular accident (CVA), unstable angina, or MI within 6 months of study
             registration

          -  History of posterior reversible encephalopathy syndrome

          -  Other malignancies unless the patient is considered to be disease-free and has
             completed therapy for the malignancy > than 6 months prior to study entry

          -  Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
             could interfere with subject's safety, provision of informed consent, or compliance to
             study procedures

          -  Concurrent use of rifampin or ketoconazole