Nivolumab and Tocilizumab for Relapsed Hematological Malignancy Post-allogeneic Transplant

• ClinicalTrials.gov Identifier: NCT03588936
• Recruitment Status: Recruiting
• First Posted: July 17, 2018
• Last Update Posted: August 26, 2019
• Sponsor: Medical College of Wisconsin
• Information provided by (Responsible Party): Nirav Shah, Medical College of Wisconsin

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Leukemia; Chronic Leukemia; Lymphoma; Myelodysplastic Syndromes	Drug: Nivolumab; Drug: Tocilizumab	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1 Study of Nivolumab in Combination With Tocilizumab for Treatment of Patients With Relapsed Hematological Malignancies Post-allogeneic Transplant
• Actual Study Start Date: September 14, 2018
• Estimated Primary Completion Date: August 1, 2021
• Estimated Study Completion Date: August 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Nivolumab and Tocilizumab; 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.	Drug: Nivolumab; Patients will receive Nivolumab at one of two dose levels every 2 weeks for 4 treatments.; Other Name: OPDIVO; Drug: Tocilizumab; Patients will receive 2 doses of tocilizumab; Other Name: ACTEMRA

Outcome Measures

Primary Outcome Measures :

1. 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) ]
   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 :

1. Response Rates [ Time Frame: Evaluate at the end of study treatment (approximately 2 months) ]
   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.
2. Overall Survival [ Time Frame: Up to 1 year from beginning of treatment ]
   Will measure survival of patients after treatment
3. Progression Free Survival [ Time Frame: Up to 1 year from beginning of treatment ]
   Determine the number of patients alive and in remission after treatment
4. Duration of response in responding patients [ Time Frame: Up to 1 year from the beginning of treatment ]
   Time that a patient's disease remains stable

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Medical College of Wisconsin Cancer Center Clinical Trials Office; 414-805-8900; cccto@mcw.edu

Locations

United States, Wisconsin

Froedtert Hospital and the Medical College of Wisconsin; Recruiting

Milwaukee, Wisconsin, United States, 53226

Contact: Froedtert Hospital and the Medical College of Wisconsin 866-680-0505 ext 8900 cccto@mcw.edu

Sponsors and Collaborators

Medical College of Wisconsin

Investigators

• Principal Investigator: Nirav Shah, MD; Medical College of Wisconsin

More Information

• Responsible Party: Nirav Shah, Assistant Professor, Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT03588936 History of Changes
• Other Study ID Numbers: PRO32525
• First Posted: July 17, 2018
• Last Update Posted: August 26, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Leukemia; Myelodysplastic Syndromes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents