Clinical Trials /

Testing the Addition of an Anti-cancer Drug, Copanlisib, to the Usual Immunotherapy (Nivolumab With or Without Ipilimumab) in Patients With Advanced Solid Cancers That Have Changes in the Following Genes: PIK3CA and PTEN

NCT04317105

Description:

This phase I/II trial studies the side effects and best dose of copanlisib when given together with nivolumab and ipilimumab and to see how well they work in treating patients with solid cancers that have spread to other places in the body (advanced) and have changes in PIK3CA and PTEN genes. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The addition of copanlisib to usual immunotherapy may work better in treating patients with solid cancers compared to usual immunotherapy alone.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, Copanlisib, to the Usual Immunotherapy (Nivolumab With or Without Ipilimumab) in Patients With Advanced Solid Cancers That Have Changes in the Following Genes: PIK3CA and PTEN
  • Official Title: A Phase I/II Biomarker Driven Combination Trial of Copanlisib and Immune Checkpoint Inhibitors in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-01917
  • SECONDARY ID: NCI-2020-01917
  • SECONDARY ID: NCI10221
  • SECONDARY ID: 10221
  • SECONDARY ID: 10221
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT04317105

Conditions

  • Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Unresectable Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
Copanlisib Hydrochloride5-Pyrimidinecarboxamide, 2-Amino-N-(2,3-dihydro-7-methoxy-8-(3-(4-morpholinyl)propoxy)imidazo(1,2-C)quinazolin-5-yl)-, Hydrochloride (1:2), Aliqopa, BAY 80-6946 Dihydrochloride, BAY-80-6946 Dihydrochloride, Copanlisib DihydrochlorideTrial I (copanlisib, nivolumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTrial II (copanlisib, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTrial I (copanlisib, nivolumab)

Purpose

This phase I/II trial studies the side effects and best dose of copanlisib when given together with nivolumab and ipilimumab and to see how well they work in treating patients with solid cancers that have spread to other places in the body (advanced) and have changes in PIK3CA and PTEN genes. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The addition of copanlisib to usual chemotherapy may work better in treating patients with solid cancers compared to usual chemotherapy alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate safety and confirm the combination recommended phase 2 dose (RP2D) of the
      combination of copanlisib, nivolumab (and ipilimumab) in patients with molecularly-selected
      advanced solid tumors.

      SECONDARY OBJECTIVES:

      I. To observe and record antitumor activity. II. To assess clinical benefit of copanlisib in
      combination with nivolumab (and ipilimumab) in patients with molecularly-selected advanced
      solid tumors, as measured by objective response (OR) = complete response (CR) + partial
      response (PR).

      III. To assess overall duration of response (DoR), progression free survival (PFS), and
      overall survival (OS).

      IV. To assess immune-modulatory changes associated with copanlisib-induced PI3K inhibition
      and combination of copanlisib and nivolumab (and ipilimumab).

      V. To correlate molecular alterations in the PI3K-AKT pathway and treatment induced
      immune-modulatory changes with objective response (OR).

      EXPLORATORY OBJECTIVES:

      I. To perform molecular profiling assays on malignant and normal tissues, including, but not
      limited to, whole exome sequencing (WES), ribonucleic acid (RNA) sequencing, reverse phase
      protein array (RPPA), circulating tumor deoxyribonucleic acid (DNA) analysis, and immune
      profiling in order to:

      Ia. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by
      which treatment may be assigned.

      Ib. Identify resistance mechanisms using genomic DNA- and RNA-based assessment platforms.

      II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
      and future research.

      III. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
      analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
      Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

      OUTLINE: This is a phase I, dose-escalation study of copanlisib followed by a phase II study.
      Patients are assigned to 1 of 2 trials.

      TRIAL I: Patients receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1,
      8, and 15 of cycle 1. Beginning in cycle 2, patients also receive nivolumab IV over 60
      minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      TRIAL II: Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 of
      cycle 1. Beginning in cycle 2, patients also receive nivolumab IV over 60 minutes on day 1
      and ipilimumab IV over 90 minutes every 8 weeks for 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 at 30 days and then every 3-6
      months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Trial I (copanlisib, nivolumab)ExperimentalPatients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 of cycle 1. Beginning in cycle 2, patients also receive nivolumab IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Copanlisib Hydrochloride
  • Nivolumab
Trial II (copanlisib, nivolumab, ipilimumab)ExperimentalPatients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 of cycle 1. Beginning in cycle 2, patients also receive nivolumab IV over 60 minutes on day 1 and ipilimumab IV over 90 minutes every 8 weeks for 4 doses. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Copanlisib Hydrochloride
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed malignancy that is metastatic or
             unresectable and for which standard curative measures do not exist or are no longer
             effective

          -  Patients must be >= 4 weeks beyond treatment with any chemotherapy or other
             investigational therapy to include hormonal, biological, or targeted agents; or at
             least 5 half-lives from hormonal, biological, or targeted agents, whichever is shorter
             at the time of treatment initiation

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL

          -  Platelets >= 100,000 / mcL

          -  Hemoglobin >= 9 g/dL

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
             creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatine clearance [CrCl]) >= 60 mL/min for subject with creatinine
             levels > 1.5 x institutional ULN (creatinine clearance should be calculated per
             institutional standard)

          -  Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 x ULN

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR =<
             5 x ULN for subjects with liver metastases

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants

          -  Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
             (RECIST) version (v)1.1

          -  Glycosylated hemoglobin (HbA1c) =< 8.5% at screening

          -  Women of child-bearing potential MUST have a negative serum or urine human chorionic
             gonadotropin (HCG) test within 24 hours of study enrollment unless prior tubal
             ligation (>= 1 year before screening), total hysterectomy or menopause (defined as 12
             consecutive months of amenorrhea). Patients should not become pregnant or breastfeed
             while on this study. Sexually active patients must agree to use dual contraception for
             the duration of study participation and for 7 months after the last dose of study
             treatment for women of childbearing potential and 5 months for men with partners that
             are women of childbearing potential

          -  Patients need to have biopsiable disease to enroll on Trial 1 (copanlisib + nivolumab)

          -  Patients in PIK3CA mutant and PTEN mutant dose expansion cohorts will need to have at
             least one actionable molecular aberration in the PIK3CA or PTEN gene (local testing in
             Clinical Laboratory Improvement Act [CLIA]-certified laboratory will be accepted).
             Recruitment of patients with PIK3CA and PTEN molecular aberrations in the dose
             escalation phase is encouraged but not mandated

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

          -  Patients who have previously received PD-1/PD-L1/PI3K inhibitors will be eligible for
             this study

        Exclusion Criteria:

          -  Patients who are receiving any other investigational agents

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

          -  Known active hepatitis B or hepatitis C infection. All patients must be screened for
             hepatitis B virus (HBV) and hepatitis C virus (HCV) up to 28 days prior to study drug
             start using the routine hepatitis virus lab panel. Patients positive for hepatitis B
             virus surface antigen (HBsAg) and/or hepatitis B virus core antibody (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 RNA

          -  Human immunodeficiency virus (HIV)-infected (HIV1/2 antibody-positive) patients may
             participate IF they meet all the following eligibility requirements:

               -  They must be on an anti-retroviral regimen with evidence of at least two
                  undetectable viral loads within the past 6 months on this same regimen; the most
                  recent undetectable viral load must be within the past 12 weeks

               -  They must have a CD4 count >= 250 cells/mcL over the past 6 months on this same
                  anti-retroviral regimen and must not have had a CD4 count < 200 cells/ mcL over
                  the past 2 years, unless it was deemed related to the cancer and/or
                  chemotherapy-induced bone marrow suppression

                    -  For patients who have received chemotherapy in the past 6 months, a CD4
                       count < 250 cells/mcL during chemotherapy is permitted as long as viral
                       loads were undetectable during this same chemotherapy

               -  They must have an undetectable viral load and a CD4 count >= 250 cells/mcL within
                  7 days of enrollment

               -  They must not be currently receiving prophylactic therapy for an opportunistic
                  infection and must not have had an opportunistic infection within the past 6
                  months

          -  Active infection requiring intravenous (IV) antibiotics or other uncontrolled
             intercurrent illness requiring hospitalization

          -  Active autoimmune disease or history of autoimmune disease that might recur, which may
             affect vital organ function or require immune suppressive treatment including systemic
             corticosteroids. Exceptions include vitiligo, type I diabetes mellitus, endocrine
             deficiencies including thyroiditis managed with replacement hormones including
             physiologic corticosteroids, Sjogren's syndrome

          -  Inability to comply with the study and follow-up procedures

          -  History of cerebrovascular accident (CVA), myocardial infarction, or unstable angina
             within the previous 6 months before starting therapy

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin that has undergone curative therapy, or in situ cervical cancer

          -  Has a known psychiatric or substance abuse disorder that would interfere with
             cooperation with the requirements of the trial

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least 4 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 trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability

          -  Patients with HbA1c > 8.5%

               -  Note: For patients with newly diagnosed diabetes mellitus that cannot meet
                  protocol requirements, a single re-screening (which includes all screening
                  procedures) should be performed when the patient's diabetes is controlled and can
                  meet protocol eligibility requirement for HbA1c

          -  History of any clinically significant drug allergy or hypersensitivity to compounds of
             similar chemical or biologic composition to copanlisib, PI3K inhibitors, nivolumab,
             and ipilimumab (such as anaphylaxis or hepatotoxicity)

          -  Has known history of psoriasis even if not active at the time given may pose
             additional risks of immune activation with the combination regimen

          -  Patients with live vaccines and live, attenuated vaccines (prohibited for 30 days
             prior to study agents, during the study, and for 100 days after the last dose of study
             drug). Patients with inactivated vaccines are permitted

          -  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 include:

               -  Herbal medications/preparations (except vitamins)

               -  Anti-arrhythmic therapy other than beta blockers or digoxin

          -  Patients will 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. Inhaled or
             topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease. Patients are permitted to
             use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
             (with minimal systemic absorption). A brief course of corticosteroids for prophylaxis
             (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,
             delayed-type hypersensitivity reaction caused by contact allergen) is permitted. The
             use of corticosteroids as antiemetics prior to copanlisib administration will not be
             allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events and serious adverse events
Time Frame:At 30 days after last dose of study drug and every 3-6 months for up to 2 years
Safety Issue:
Description:Adverse events and serious adverse events will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Measure:Objective response (OR) rate (complete response [CR] + partial response [PR])
Time Frame:Up to 2 years post-treatment
Safety Issue:
Description:Will estimate OR rate with 95% confidence intervals. Inferences and estimation are based on the exact binomial test.
Measure:Clinical benefit rate (OR + stable disease [SD] > 6 months)
Time Frame:Up to 2 years post-treatment
Safety Issue:
Description:
Measure:Progression free survival (PFS)
Time Frame:Until disease progression, start of a new cancer therapy, or up to 2 years after the last dose of study drugs, whichever comes first
Safety Issue:
Description:Will use the Kaplan-Meier method to estimate PFS.
Measure:Overall survival (OS)
Time Frame:Until disease progression, start of a new cancer therapy, or up to 2 years after the last dose of study drugs, whichever comes first
Safety Issue:
Description:Will use the Kaplan-Meier method to estimate OS.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

July 18, 2020