A Phase I/II Biomarker Driven Combination Trial of Copanlisib and Immune Checkpoint Inhibitors in Patients With Advanced Solid Tumors

  • days left to enroll
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 16 October 2022
monoclonal antibodies
measurable disease
international normalized ratio
neutrophil count
liver metastasis
tumor cells
solid tumour
antibody therapy
glycosylated hemoglobin


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.



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.


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).


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.

Condition Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm, Unresectable Malignant Solid Neoplasm
Treatment Ipilimumab, Nivolumab, Copanlisib Hydrochloride
Clinical Study IdentifierNCT04317105
SponsorNational Cancer Institute (NCI)
Last Modified on16 October 2022


Yes No Not Sure

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
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of copanlisib in combination with nivolumab (and ipilimumab) in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
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 dose escalation and expansion of all arms must have actionable mutations in either PIK3CA hotspot (E542, E545, or H1047 are accepted) or PTEN (except for specific wild type cohorts). Local testing in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory will be accepted. Only mutations that have been recognized as actionable by the MD Anderson Precision Oncology Decision Support (PODS) team will be accepted
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 not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months
They must have an undetectable viral load and a CD4 count >= 250 cells/mcL within
days of enrollment
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
Active infection requiring intravenous (IV) antibiotics or other uncontrolled
Inability to comply with the study and follow-up procedures
intercurrent illness requiring hospitalization
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
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
History of any clinically significant drug allergy or hypersensitivity to compounds of
Herbal medications/preparations (except vitamins)
similar chemical or biologic composition to copanlisib, PI3K inhibitors
nivolumab, and ipilimumab (such as anaphylaxis or hepatotoxicity)
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
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