Description:
This is a phase 1, interventional single arm, open label, treatment study designed to
evaluate the safety combination programmed cell death protein 1 (PD-1) and interleukin 6
(IL-6) inhibition in participants with relapsed disease post-allogeneic transplant.
Title
- Brief Title: Nivolumab and Tocilizumab for Relapsed Hematological Malignancy Post-allogeneic Transplant
- Official Title: Phase 1 Study of Nivolumab in Combination With Tocilizumab for Treatment of Patients With Relapsed Hematological Malignancies Post-allogeneic Transplant
Clinical Trial IDs
- ORG STUDY ID:
PRO32525
- NCT ID:
NCT03588936
Conditions
- Acute Leukemia
- Chronic Leukemia
- Lymphoma
- Myelodysplastic Syndromes
Interventions
Drug | Synonyms | Arms |
---|
Nivolumab | OPDIVO | Nivolumab and Tocilizumab |
Tocilizumab | ACTEMRA | Nivolumab and Tocilizumab |
Purpose
This is a phase 1, interventional single arm, open label, treatment study designed to
evaluate the safety combination PD-1 and IL-6 inhibition in patients with relapsed disease
post-allogeneic transplant.
Detailed Description
Study disease: Hematologic malignancies including, but not exclusive to,acute/chronic
leukemia, lymphoma, and myelodysplastic syndrome that has relapsed after allogeneic
transplant.
Study Rationale: Phase 1 Safety/Dose Finding Study: To determine the safety and maximum
tolerated dose of Nivolumab in combination with Tocilizumab.
Study Agent Description:
Tocilizumab is a monoclonal antibody and immunosuppressant; specifically, tocilizumab is an
interleukin-6 (IL-6) receptor antagonist.
Nivolumab is a human immunoglobulin IgG4 monoclonal antibody that binds to the PD-1 receptor
of T cells blocking its interaction with PD-L1 and PD-L2, thereby enhancing T-cell
proliferation and allowing the immune system to attack the tumor.
Number of Subjects: A maximum of 12 patients will be enrolled on this Phase 1 study.
Duration of Follow-up: Patients will be followed for up to one year post-treatment for
survival and response.
Trial Arms
Name | Type | Description | Interventions |
---|
Nivolumab and Tocilizumab | Experimental | Patient will receive tocilizumab 8 mg/kg IV (max dose 800 mg) on Day 0. On Day 1 patients will receive nivolumab IV (0.25 mg/kg or 0.5 mg/kg based on dose escalation design).
Nivolumab will be given every ~2 weeks for up to 4 doses and a second dose of Tocilizumab will be given on ~Day 29 on the same day as Dose # 3 of Nivolumab. | |
Eligibility Criteria
1. Age≥18 years with hematological malignancies who have undergone allogeneic transplant
for hematological malignancy and are ≥180 days post-transplant.
2. Relapsed disease post-allogeneic transplant defined as follows i. Acute or Chronic
Leukemia or myelodysplastic or myeloproliferative disorders or NK cell neoplasms: Bone
marrow (BM) with ≥5% disease involvement or peripheral blood evidence of overt relapse
ii. Lymphoma: BM evidence of relapsed/persistent disease or PET/CT or CT evidence of
persistent/progressive lymphadenopathy consistent with active lymphoma. Active disease
defined as nodal lesions ≥ 20 mm in the long axis or extranodal lesions≥10 mm in long
and short axis or bone marrow involvement that is biopsy proven
3. Karnofsky performance status ≥70 (See Appendix A for details)
4. Creatinine Clearance≥60 ml/min
5. Adequate hepatic function, defined as AST and ALT ≤3 x ULN. Serum bilirubin and
alkaline phosphatase ≤3x x ULN, or considered not clinically significant (e.g.
Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease.
6. Without evidence of active acute or chronic GVHD
7. Off all immunosuppression and corticosteroids (other than replacement dose steroids
defined as equivalent to a maximum of 10 mg Prednisone daily) for ≥28 days from first
treatment.
8. Off all disease targeted treatments for ≥10 days to first treatment day
9. Able to provide written informed consent
10. Women of child-bearing potential and men must agree to use adequate contraception for
the duration of study participation and for 120 days after the last treatment with
nivolumab.
11. No FDA approved, more appropriate therapies available for disease control as
determined by the treating physician
Exclusion Criteria
1. Positive beta-HCG in female of child-bearing potential
2. CD3 donor chimerism <5% within 4 weeks of starting study treatment
3. Prior administration of donor lymphocyte infusion post-allogeneic transplant within
the last 6 months of study treatment
4. History of or active autoimmune disease, or other syndrome that requires systemic
steroids.
5. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab.
6. Uncontrolled or active infections on treatment
7. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.
8. Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5 from any
previous treatment unless it is felt to be due to underlying disease.
9. Concurrent use of investigational therapeutic agents or enrollment on another
therapeutic clinical trial at any institution.
a. Minimum of 4 weeks from last dose of investigational agent
10. Prior exposure to PD-1 or CTLA4 antibodies in the post-allogeneic transplant setting.
Patients who received such agents pre-allogeneic transplant will NOT be excluded.
11. Prior exposure to daratumumab in the post-allogeneic transplant setting within 2
months of start date of treatment with this investigational protocol. Patients who
received this agent pre-allogeneic transplant will NOT be excluded
12. Concurrent therapies targeted at disease relapse. However, previous treatments for
relapsed disease are allowed.
13. Concurrent active malignancy (exceptions: treated solid malignancy in >2 years'
remission, treated basal or squamous cell carcinomas of the skin)
14. History of Crohn's disease or ulcerative colitis
15. History of demyelinating disorder
16. Prior intolerance or allergy to Tocilizumab
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Maximum Tolerated Dose among Two Candidate Doses of Nivolumab in Combination with Tocilizumab |
Time Frame: | Up to 4 weeks after last dose of study treatment (approximately 3 months) |
Safety Issue: | |
Description: | Determine the safety and the maximum tolerated dose among two candidate doses of nivolumab in combination with tocilizumab for treatment of relapsed hematological malignancy post-allogeneic transplant. This will be measured by the number of adverse events as defined by the NCI CTCAE version 4.03 non-hematologic ≥ grade 3-5 signs/symptoms or by the development of steroid refractory grade 2-4 graft-versus-host disease or severe chronic graft-versus-host disease |
Secondary Outcome Measures
Measure: | Response Rates |
Time Frame: | Evaluate at the end of study treatment (approximately 2 months) |
Safety Issue: | |
Description: | Since patients with a variety of histologies will be treated - response will be assessed using disease appropriate imaging/marrow and international consensus criteria most applicable to the disease. |
Measure: | Overall Survival |
Time Frame: | Up to 1 year from beginning of treatment |
Safety Issue: | |
Description: | Will measure survival of patients after treatment |
Measure: | Progression Free Survival |
Time Frame: | Up to 1 year from beginning of treatment |
Safety Issue: | |
Description: | Determine the number of patients alive and in remission after treatment |
Measure: | Duration of response in responding patients |
Time Frame: | Up to 1 year from the beginning of treatment |
Safety Issue: | |
Description: | Time that a patient's disease remains stable |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Medical College of Wisconsin |
Last Updated
August 21, 2019