Clinical Trials /

Testing the Combination of Copanlisib, Nivolumab and Ipilimumab in Patients With Advanced Cancer and Lymphoma

NCT03502733

Description:

This phase Ib trial studies the side effects and best dose of copanlisib and nivolumab and side effects of copanlisib given together with nivolumab and ipilimumab in treating patients with solid tumors that have spread to other places in the body (advanced) or lymphoma. Copanlisib stops tumors from growing by blocking proteins that are known to be important for tumor cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ipilimumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving copanlisib together with nivolumab or with nivolumab and ipilimumab 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: Testing the Combination of Copanlisib, Nivolumab and Ipilimumab in Patients With Advanced Cancer and Lymphoma
  • Official Title: Phase Ib Study of Copanlisib in Combination With Nivolumab or With Nivolumab and Ipilmumab

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-02249
  • SECONDARY ID: NCI-2017-02249
  • SECONDARY ID: NCI CC 18-C-0122
  • 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
  • Recurrent Malignant Solid Neoplasm
  • Unresectable Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
CopanlisibBAY 80-6946, PI3K Inhibitor BAY 80-6946Treatment (copanlisib, nivolumab, ipilimumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (copanlisib, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (copanlisib, nivolumab, ipilimumab)

Purpose

This phase Ib trial studies the side effects and best dose of copanlisib and nivolumab and side effects of copanlisib given together with nivolumab and ipilimumab in treating patients with solid tumors that have spread to other places in the body (advanced) or lymphoma. Copanlisib stops tumors from growing by blocking proteins that are known to be important for tumor cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ipilimumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving copanlisib together with nivolumab or with nivolumab and ipilimumab 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.

      II. To evaluate the safety and tolerability of copanlisib combined with nivolumab and
      ipilimumab in patients with advanced solid tumors and lymphomas.

      EXPLORATORY OBJECTIVES:

      I. Evaluate the effect of the doublet and triplet combinations on markers of anti-tumor
      immunity in circulating immune cells 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.

      DOUBLET TREATMENT PLAN: 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. Cycles repeat every
      28 days in the absence of disease progression or unacceptable toxicity.

      TRIPLET TREATMENT PLAN: Patients receive copanlisib IV over 1 hour on days 1, 8, and 15,
      nivolumab IV over 30 minutes on day 1 or on days 1 and 15. Beginning cycle 2, patients also
      receive ipilimumab IV over 90 minutes on day 1 for a total of 4 doses. Cycles 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, ipilimumab)ExperimentalDOUBLET TREATMENT PLAN: Patients 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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. TRIPLET TREATMENT PLAN: Patients receive copanlisib IV over 1 hour on days 1, 8, and 15, nivolumab IV over 30 minutes on day 1 or on days 1 and 15. Beginning cycle 2, patients also receive ipilimumab IV over 90 minutes on day 1 for a total of 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Copanlisib
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically documented metastatic, recurrent, or locally
             unresectable solid tumors which have progressed after one line of therapy, or for
             which no curative therapy is available. Patients with lymphoma who have received
             adequate exposure to standard of care therapy and for whom no curative therapy is
             available are also eligible (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 (solid tumor patients) >= 75,000/mcL (lymphoma patients)

          -  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

          -  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 who are therapeutically treated with an agent such as warfarin or heparin
             will be allowed to participate provided that their medication dose is stable, and
             international normalized ratio/partial thromboplastin time (INR/PTT) remains stable
             within the recommended therapeutic range

          -  Patients must have left ventricular ejection fraction (LVEF) >= 50%

          -  The effects of nivolumab, copanlisib and ipilimumab on the developing human fetus are
             unknown, and there is potential for teratogenic or abortifacient effects. For this
             reason, women of child-bearing potential 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 5 months 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. Men treated or enrolled on this protocol must also agree to use adequate
             contraception prior to study entry, for the duration of study participation, and for 7
             months after completion of study treatment

          -  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 are ineligible. Uncontrolled arterial
             hypertension is defined as an average blood pressure of > 140 mm Hg systolic and/or >
             90 mm Hg diastolic over 3 measurements, taken over the course of one clinic visit at
             intervals of >=30 minutes. Patients with well-controlled arterial hypertension are
             eligible

          -  Patients with uncontrolled Type I or II diabetes mellitus, defined as fasting blood
             glucose of >160 mg/dL and glycosylated hemoglobin measurement (HgA1c) >8.5%, are
             ineligible. Patients with fasting blood glucose >160 mg/dL may be eligible if the
             HgA1c < 8.5%, per principal investigator (PI) discretion. Patients with
             well-controlled 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 are not eligible if they have had 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 immune checkpoint pathways. Patients should therefore be
             excluded if they have had prior treatment with the combination of a PI3K inhibitor and
             a PD-1 inhibitor; however, prior treatment with a PI3K/AKT/mTOR inhibitor (without the
             addition of a checkpoint inhibitor) is allowed. Patients that have had prior CAR
             T-cell therapy are eligible

          -  Patients who have previously received one line of immunotherapy (including checkpoint
             inhibitors) are eligible; however, patients previously receiving ipilimumab +
             nivolumab combination therapy are excluded. Patients who received prior therapy with a
             checkpoint inhibitor and were taken off drug for serious adverse events are excluded.
             Prior treatment with a PI3K/AKT/mTOR inhibitor, or prior CAR T-cell therapy is allowed

          -  Copanlisib is primarily metabolized by CYP3A4. Therefore, 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
             from 14 days prior to enrollment until the end of the study. Other medications that
             are prohibited while on copanlisib treatment:

               -  Herbal medications/preparations (except for vitamins)

               -  Anti-arrhythmic therapy other than beta blockers or digoxin

          -  Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of
             highly active antiretroviral therapy (HAART), no clinically significant drug-drug
             interactions are anticipated with the current HAART regimen, and viral load is
             undetectable. Patients on HAART regimens that include CYP3A4 inhibitors (e.g.
             ritonavir or cobicistat) are excluded. All patients must be screened for HIV up to 28
             days prior to enrollment

          -  Hepatitis B (HBV) or hepatitis C (HCV) infection. All patients must be screened for
             HBV and HCV up to 28 days prior to enrollment using the routine hepatitis virus lab
             panel. Patients positive for hepatitis B virus surface antigen measurement (HBsAg)
             and/or hepatitis B virus core antibody measurement (HBcAb) will be eligible if they
             are negative for HBV DNA; these patients should receive prophylactic antiviral
             therapy. Patients positive for anti-HCV antibody will be eligible if they are negative
             for HCV ribonucleic acid (RNA)

          -  Cytomegalovirus (CMV) infection. All patients must be screened for CMV up to 28 days
             prior to enrollment. Patients that are positive for CMV DNA by polymerase chain
             reaction (PCR) are not eligible for the study

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to copanlisib, PI3K inhibitors, nivolumab, or ipilimumab

          -  Patients with active autoimmune disease requiring systemic treatment within the past 3
             months, a documented history of clinically severe autoimmune disease, or a syndrome
             that requires systemic steroids or immunosuppressive agents are not eligible. Patients
             with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
             Patients that require intermittent use of bronchodilators or local steroid injections
             will not be excluded from the study. Patients with hypothyroidism and stable on
             hormone replacement or Sjogren's syndrome will not be excluded from the study

          -  Pregnant or breastfeeding women will be excluded from participation in this trial, as
             there is no significant preclinical information regarding the effects of nivolumab,
             copanlisib, and ipilimumab, on a fetus or newborn infant
      
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.

Details

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

Last Updated

October 2, 2020