Clinical Trials /

Copanlisib and Nivolumab in Treating Patients With Metastatic Solid Tumors or Lymphoma

NCT03502733

Description:

This phase Ib trial studies the side effects and best dose of copanlisib and nivolumab in treating patients with solid tumors that have spread to other places in the body or lymphoma. Copanlisib stops tumors from growing by blocking proteins that are known to be important for tumor cell growth. Monoclonal antibodies, such as nivolumab, may unblock the immune system so that it can recognize and attack tumor cells. Giving copanlisib and nivolumab may work better in treating patients with solid tumors or lymphoma.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib and Nivolumab in Treating Patients With Metastatic Solid Tumors or Lymphoma
  • Official Title: Phase Ib Combination Study of Copanlisib and Nivolumab in Advanced Solid Tumors and Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-02249
  • SECONDARY ID: NCI-2017-02249
  • SECONDARY ID: 10145
  • SECONDARY ID: 10145
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT03502733

Conditions

  • Ann Arbor Stage III Lymphoma
  • Ann Arbor Stage IV Lymphoma
  • Metastatic Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
CopanlisibBAY 80-6946, PI3K Inhibitor BAY 80-6946Treatment (copanlisib, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (copanlisib, nivolumab)

Purpose

This phase Ib trial studies the side effects and best dose of copanlisib and nivolumab in treating patients with solid tumors that have spread to other places in the body or lymphoma. Copanlisib stops tumors from growing by blocking proteins that are known to be important for tumor cell growth. Monoclonal antibodies, such as nivolumab, may unblock the immune system so that it can recognize and attack tumor cells. Giving copanlisib and nivolumab may work better in treating patients with solid tumors or lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the safety, tolerability, and the recommended phase 2 dose (RP2D) of
      copanlisib and nivolumab combination in patients with advanced solid tumors and lymphomas.

      SECONDARY OBJECTIVES:

      I. Evaluate the effect of the copanlisib and nivolumab combination on markers of anti-tumor
      immunity in circulating immune cells, circulating tumor cells (CTCs), and pre- and
      post-treatment tumor biopsies.

      II. Evaluate the effect of the combination on biomarkers of AKT inhibition, deoxyribonucleic
      acid (DNA) damage (gammaH2AX, pNbs1, Rad51), apoptosis, and epithelial-mesenchymal transition
      in CTCs and pre- and post- treatment tumor biopsies.

      III. Assess preliminary antitumor activity of the combination.

      OUTLINE: This is a dose-escalation study.

      Patients receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15 and nivolumab
      IV over 30 minutes on day 1 or on days 1 and 15. Courses repeat every 28 days in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (copanlisib, nivolumab)ExperimentalPatients receive copanlisib IV over 1 hour on days 1, 8, and 15 and nivolumab IV over 30 minutes on day 1 or on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Copanlisib
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically documented metastatic solid tumors which have
             progressed after one line of therapy, or lymphoma which has progressed after all Food
             and Drug Administration (FDA)-approved therapy; this trial will enroll a minimum of 5
             lymphoma patients

          -  Patients must have measurable or evaluable disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Leukocytes >= 2,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =<1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])
             /alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x
             institutional ULN

          -  Serum creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 50 mL/min/1.73
             m^2 by Cockcroft-Gault

          -  Amylase/lipase =< 1.5 x institutional ULN (without symptoms of pancreatitis)

          -  Any prior therapy must have been completed >= 4 weeks (6 weeks for nitrosoureas and
             mitomycin C) or, if known, >= 5 half-lives of the prior agent (whichever is shorter)
             prior to enrollment on protocol (minimum of 1 week between prior therapy and study
             enrollment), and the participant must have recovered to eligibility levels from prior
             toxicity; prior definitive radiation should have been completed >= 4 weeks or
             palliative radiation should have been completed >= 2 weeks prior to study enrollment
             and all associated toxicities resolved to eligibility levels; patients must be >= 2
             weeks since any investigational agent administered as part of a phase 0 study (where a
             sub-therapeutic dose of drug is administered) at the principal investigator's (PI's)
             discretion, and should have recovered to grade 1 or baseline from any toxicities

          -  Patients who have had prior monoclonal antibody therapy must have completed that
             therapy >= 6 weeks (or 3 half-lives of the antibody, whichever is shorter) prior to
             enrollment on protocol (minimum of 1 week between prior therapy and study enrollment)

          -  Patients that have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2,
             anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
             co-stimulation or immune checkpoint pathways are eligible, unless they discontinued
             such therapy due to toxicity

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, during
             the treatment portion of the study, and for a minimum of 8 after the last dose of
             study drug; should a woman become pregnant or suspect she is pregnant while she or her
             partner is participating in this study, she should inform her treating physician
             immediately

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Willingness to provide blood and new tumor biopsy samples for research purposes if on
             the expansion phase of the study

        Exclusion Criteria:

          -  Patients who are receiving any other investigational agents

          -  Patients with clinically significant illnesses which would compromise participation in
             the study, including but not limited to active or uncontrolled infection, immune
             deficiencies, hepatitis B, hepatitis C, active tuberculosis, uncontrolled asthma,
             symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac
             arrhythmia, myocardial infarction within the past 6 months, cerebral vascular
             accident/stroke within the past 6 months, or psychiatric illness/social situations
             that would limit compliance with study requirements

          -  Patients with known brain metastases or carcinomatous meningitis are excluded from
             this clinical trial, with the exception of patients whose brain metastatic disease
             status has remained stable for >= 1 month after treatment of the brain metastases;
             patients on anti-seizure medications may be enrolled at the discretion of the
             principal investigator

          -  Patients with blood oxygen saturation < 90% at rest; patients must not have
             symptomatic interstitial lung disease, pneumonitis, or known pulmonary fibrosis

          -  Patients with uncontrolled arterial hypertension despite optimal medical management or
             uncontrolled type I or II diabetes mellitus; patients with well-controlled arterial
             hypertension or diabetes mellitus are eligible

          -  Patients are not eligible if they have had or are planned for solid organ transplant
             or allogeneic hematopoietic stem cell transplant

          -  Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days of study drug administration; however,
             systemic corticosteroids may be indicated after starting the study drugs to treat
             immune-related adverse reactions; inhaled or topical steroids and adrenal replacement
             doses >10 mg daily prednisone equivalents are permitted in the absence of active
             autoimmune disease

          -  Patients should be excluded if they have had prior treatment with the combination of a
             PI3K inhibitor and a PD-1 inhibitor

          -  The concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole,
             clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) and strong inducers
             of CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) is
             not permitted; it is important to regularly consult a frequently-updated medical
             reference for a list of drugs to avoid or minimize use of; Patient Drug Information
             Handout and Wallet Card should be provided to patients; as part of the
             enrollment/informed consent procedures, the patient will be counseled on the risk of
             interactions with other agents, and what to do if new medications need to be
             prescribed or if the patient is considering a new over-the-counter medicine or herbal
             product

          -  Patients who are known to be human immunodeficiency virus (HIV)-positive at
             registration are eligible at the time of registration as long as:

               -  CD4+ cell count >= 250 cells/mm^3

               -  If patient is on antiretroviral therapy, there must be minimal interactions or
                  overlapping toxicity of the antiretroviral therapy with the study drugs; once
                  daily combinations that use pharmacologic boosters may not be used

               -  No history of non-malignancy acquired immune deficiency syndrome (AIDS)-defining
                  conditions other than historical low CD4+ cell counts

          -  Pregnant or breastfeeding women will be excluded from participation in this trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D) of copanlisib and nivolumab combination
Time Frame:Up to 28 days
Safety Issue:
Description:Will be defined as dose limiting toxicity in =< 1 out of 6 patients at highest dose level below the maximally administered dose.

Secondary Outcome Measures

Measure:Markers of anti-tumor immunity assessed in circulating immune cells, circulating tumor cells (CTCs), and pre- and post-treatment tumor biopsies
Time Frame:Up to 2 years
Safety Issue:
Description:Evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.
Measure:Biomarkers of AKT inhibition, deoxyribonucleic acid damage (gammaH2AX, pNbs1, Rad51), apoptosis, and epithelial-mesenchymal transition assessed in CTCs and pre- and post- treatment tumor biopsies
Time Frame:Up to 2 years
Safety Issue:
Description:Evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.
Measure:Preliminary antitumor activity
Time Frame:Up to 2 years
Safety Issue:
Description:Evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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