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
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
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.
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.
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 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 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