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
