Clinical Trials /

Copanlisib, Olaparib, and Durvalumab in Treating Patients With Metastatic or Unresectable Solid Tumors

NCT03842228

Description:

This phase Ib trial studies side effects and best dose of copanlisib and olaparib when given together with durvalumab, and how well they work in treating patients with solid tumors that have spread to other places in the body or cannot be removed by surgery. Copanlisib and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combinations of copanlisib and olaparib or copanlisib, olaparib, and durvalumab may work better in treating patients with solid tumors compared to usual treatments such as surgery, radiation, or other chemotherapy drugs.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib, Olaparib, and Durvalumab in Treating Patients With Metastatic or Unresectable Solid Tumors
  • Official Title: A Phase 1b Biomarker-Driven Combination Trial of Copanlisib, Olaparib, and MEDI4736 (Durvalumab) in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-00601
  • SECONDARY ID: NCI-2019-00601
  • SECONDARY ID: NCI10217
  • SECONDARY ID: 10217
  • SECONDARY ID: 10217
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT03842228

Conditions

  • Advanced Malignant Solid Neoplasm
  • ARID1A Gene Mutation
  • ATM Gene Mutation
  • ATRX Gene Mutation
  • BARD1 Gene Mutation
  • BRCA1 Gene Mutation
  • BRCA2 Gene Mutation
  • BRIP1 Gene Mutation
  • CDK12 Gene Mutation
  • CHEK1 Gene Mutation
  • CHEK2 Gene Mutation
  • FANCA Gene Mutation
  • FANCL Gene Mutation
  • Metastatic Malignant Solid Neoplasm
  • MRE11 Gene Mutation
  • MSH2 Gene Mutation
  • PALB2 Gene Mutation
  • PARP1 Gene Mutation
  • PIK3CA Gene Mutation
  • POLD1 Gene Mutation
  • PPP2R2A Gene Mutation
  • PTEN Gene Mutation
  • RAD51B Gene Mutation
  • RAD51C Gene Mutation
  • RAD51D Gene Mutation
  • RAD54L Gene Mutation
  • Unresectable Malignant Solid Neoplasm
  • XRCC2 Gene Mutation

Interventions

DrugSynonymsArms
CopanlisibBAY 80-6946, PI3K Inhibitor BAY 80-6946Treatment (copanlisib, olaparib, and durvalumab)
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 DihydrochlorideTreatment (copanlisib, olaparib, and durvalumab)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Treatment (copanlisib, olaparib, and durvalumab)
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (copanlisib, olaparib, and durvalumab)

Purpose

This phase Ib trial studies side effects and best dose of copanlisib and olaparib when given together with durvalumab, and how well they work in treating patients with solid tumors that have spread to other places in the body or cannot be removed by surgery. Copanlisib and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combinations of copanlisib and olaparib or copanlisib, olaparib, and durvalumab may work better in treating patients with solid tumors compared to usual treatments such as surgery, radiation, or other chemotherapy drugs.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and establish the recommended phase 2 dose (RP2D) of the doublet
      combination of copanlisib and olaparib and of the triplet combination of copanlisib, olaparib
      and MEDI4736 (durvalumab) in patients with molecularly-selected solid tumors.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity of the doublet combination of copanlisib and
      olaparib, and of the triplet combination of copanlisib, olaparib and MEDI4736 (durvalumab) in
      patients with molecularly-selected advanced solid tumors, as measured by objective response
      rate (ORR) (complete response [CR] + partial response [PR]). Although the clinical benefit of
      the doublet and triplet combination of these drugs has not yet been established, the intent
      of offering this treatment is to provide a possible therapeutic benefit, and thus the patient
      will be carefully monitored for tumor response and symptom relief in addition to safety and
      tolerability.

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

      III. To assess the pharmacokinetic (PK) profiles of these combinations. IV. To assess
      immune-modulatory changes associated with these combinations. V. To correlate molecular
      alterations and immuno-modulatory changes with OR (CR+PR).

      OUTLINE: This is a dose-escalation study of copanlisib and olaparib.

      Patients receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15 and olaparib
      orally (PO) twice daily (BID). Beginning cycle 2, patients receive durvalumab IV over 1 hour
      on day 1. Cycles repeat every 28 days for 24 months 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
Treatment (copanlisib, olaparib, and durvalumab)ExperimentalPatients receive copanlisib IV over 1 hour on days 1, 8, and 15 and olaparib PO BID. Beginning cycle 2, patients receive durvalumab IV over 1 hour on day 1. Cycles repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity.
  • Copanlisib
  • Copanlisib Hydrochloride
  • Durvalumab
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  ELIGIBILITY CRITERIA FOR ENROLLMENT INTO STEPS 1, 2, AND 3

          -  Patients must have germline or somatic mutations in DDR genes: ARID1A, ATM, ATRX,
             BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCL, MRE11A, MSH2, PALB2,
             PARP1, POLD1, PP2R2A, RAD51B, RAD51C, RAD51D, RAD54L, XRCC2; or actionable mutations
             in the PTEN gene, or hotspot mutations in the PIK3CA gene

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

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

          -  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

          -  Patients in dose expansion cohorts will need to have at least one relevant molecular
             aberration (mutations in DDR genes, PTEN gene, or PIK3CA gene). Local testing in
             Clinical Laboratory Improvement Act (CLIA)-certified laboratory will be accepted,
             apart from PTEN loss by immunohistochemistry (IHC), which will need to be confirmed
             centrally prior to enrollment. Recruitment of patients with relevant molecular
             aberrations in the dose escalation phase is encouraged but not mandated

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 1 (Karnofsky >=
             60%)

          -  Hemoglobin >= 10 g/dL with no blood transfusion in the past 28 days

          -  Leukocytes >= 3,000/mcL

          -  Lipase =< 1.5 x upper limit of normal (ULN)

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 x institutional ULN

          -  Serum bilirubin =< 1.5 x institutional ULN

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN, unless liver metastases are present in which case they
             must be =< 5 x ULN

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

          -  International normalized ratio =< 1.5 x ULN

          -  Glomerular filtration rate (GFR) >= 51 mL/min, based on a 24-hour urine test for
             creatinine clearance or estimated using the Cockcroft-Gault equation

          -  Left ventricular ejection fraction (LVEF) >= 50%

          -  Patients who are therapeutically treated with an agent such as warfarin or heparin
             will be allowed to participate provided that their medication dose and international
             normalized ratio (INR)/PTT is stable

          -  Prophylactic antiemetics may be administered according to standard practice. The
             routine use of standard antiemetics, including 5-hydroxytryptamine type 3 (5-HT3)
             blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as
             needed. The use of corticosteroids as antiemetics prior to copanlisib administration
             will not be allowed

          -  Postmenopausal or evidence of non-childbearing status, a negative urine or serum
             pregnancy test within 28 days of study treatment and confirmed prior to treatment on
             day 1. Postmenopausal is defined as:

               -  Amenorrheic for 1 year or more following cessation of exogenous hormonal
                  treatments

               -  Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
                  postmenopausal range for women under 50

               -  Radiation-induced oophorectomy with last menses > 1 year ago

               -  Chemotherapy-induced menopause with > 1 year interval since last menses

               -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

          -  Women of child-bearing potential MUST have a negative serum or urine human chorionic
             gonadotropin (HCG) test 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

          -  Patients and their partners, if sexually active and of childbearing potential, must
             agree to the use of two highly effective forms of contraception in combination
             throughout the period of taking study treatment and for 6 months after last dose of
             study drug(s) to prevent pregnancy in the study patient or partner. Male patients
             should avoid donating sperm for 3 months following the last dose of olaparib

          -  Human immunodeficiency virus (HIV)-infected (HIV 1/2 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

          -  Glycosylated hemoglobin (HbA1C) of =< 8.5% at screening

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

          -  Patient is willing and able to comply with the protocol for the duration of the study,
             including undergoing treatment and scheduled visits and examinations

          -  ELIGIBILITY CRITERIA FOR ENROLLMENT INTO STEP 2 AND 3 ONLY

          -  Body weight > 30 kg

          -  Life expectancy >= 16 weeks

        Exclusion Criteria:

          -  EXCLUSION CRITERIA FOR STEPS 1, 2, AND 3

          -  Patients who are receiving any other investigational agents

          -  Other malignancy unless curatively treated with no evidence of disease for >= 5 years
             except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer
             of the cervix, ductal carcinoma in situ (DCIS), or stage 1, grade 1 endometrial
             carcinoma. A patient with a history of localized triple negative breast cancer may be
             eligible, provided the patient completed the adjuvant chemotherapy > 3 years prior to
             registration, and the patient remains free of recurrent or metastatic disease

          -  Patients with myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or with bone
             marrow findings consistent with MDS/AML

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to olaparib, copanlisib, PI3K inhibitors or MEDI4736 (durvalumab) or any
             of the excipients of any study products

          -  Concomitant use of strong CYP3A inhibitors and inducers

               -  Olaparib: concomitant use of known strong CYP3A inhibitors (e.g., itraconazole,
                  telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
                  cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or
                  moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem,
                  fluconazole, verapamil). The required washout period for strong or moderate CYP3A
                  inhibitors prior to starting olaparib is 2 weeks

               -  Because the lists of these agents are constantly changing, it is important to
                  regularly consult a frequently-updated medical reference. As part of the
                  enrollment/informed consent procedures, the patient will be counseled on the risk
                  of interactions with other agents, and what to do if new medications need to be
                  prescribed or if the patient is considering a new over-the-counter medicine or
                  herbal product

               -  Concomitant use of known strong CYP3A inducers (e.g., phenobarbital,
                  enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine,
                  nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan,
                  efavirenz, modafinil). The required washout period for strong or moderate CYP3A
                  inducers prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital
                  and 3 weeks for other agents

               -  Copanlisib: 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) are 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

               -  Because the lists of these agents are constantly changing, it is important to
                  regularly consult a frequently-updated medical reference for a list of drugs to
                  avoid or minimize use of. As part of the enrollment/informed consent procedures,
                  the patient will be counseled on the risk of interactions with other agents, and
                  what to do if new medications need to be prescribed or if the patient is
                  considering a new over-the-counter medicine or herbal product

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, uncontrolled major seizure disorder, unstable spinal cord compression,
             superior vena cava syndrome, extensive interstitial bilateral lung disease on high
             resolution computed tomography (HRCT) scan, symptomatic congestive heart failure,
             cardiac arrhythmia, or psychiatric illness/social situations that would limit
             compliance with study requirements

          -  Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
             cardiac conditions, as judged by the investigator (e.g., unstable ischemia,
             uncontrolled symptomatic arrhythmia, congestive heart failure, QT corrected by the
             Fridericia formula [QTcF] prolongation of > 500 msec, electrolyte disturbances), or
             patients with congenital long QT syndrome

          -  Women who are breast feeding or pregnant are excluded from this study because olaparib
             is a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor with the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with olaparib, breastfeeding should be discontinued if the mother is treated
             with olaparib and copanlisib +/- MEDI4736 (durvalumab)

          -  Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT)

          -  Packed red blood cell or platelet transfusion in the last 28 days prior to study entry

          -  Whole blood transfusions in the last 120 days prior to study entry. Whole blood
             transfusions performed within 120 days of study entry may interfere with blood samples
             taken for exploratory analysis

          -  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 with non-healing wound, ulcer, or bone fracture

          -  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 then patient's diabetes is controlled and
                  can meet protocol eligibility requirement for HbA1c

          -  Arterial or venous thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
             within 6 months before the start of study medication

          -  Patients with active, clinically serious infections > grade 2 (Common Terminology
             Criteria for Adverse Events [CTCAE] version [v] 5.0). Active infection including
             tuberculosis (clinical evaluation that includes clinical history, physical examination
             and radiographic findings, and tuberculosis [TB] testing in line with local practice),
             hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result),
             or hepatitis C. Patients with a past or resolved HBV infection (defined as the
             presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.
             Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
             reaction is negative for HCV ribonucleic acid (RNA). HBV/HCV screening is required 28
             days prior to starting the study drug using a routine hepatitis virus lab panel

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

          -  Patients unable to swallow orally administered medication and any medical condition or
             diagnosis that would likely impair absorption of an orally administered drug (e.g.
             gastrectomy, ileal bypass, chronic diarrhea, gastroparesis)

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial

          -  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 four 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

          -  New York Heart Association class III or IV heart disease

          -  History or concurrent interstitial lung disease of any severity and/or severely
             impaired lung function (as judged by the investigator)

          -  Uncontrolled arterial hypertension despite optimal medical management (per
             investigator's opinion)

          -  EXCLUSION STEPS 2 AND 3 ONLY

          -  Patients who have not recovered from grade >= 2 adverse events due to prior
             anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory
             values defined in the inclusion criteria

               -  Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis
                  after consultation with the study physician

          -  Major surgical procedure (as defined by the investigator) within 28 days prior to the
             first dose of investigational product (IP).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum-tolerated dose (MTD) of copanlisib and olaparib
Time Frame:Up to 28 days
Safety Issue:
Description:Will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015; Yuan et al., 2016) to determine the MTD.

Secondary Outcome Measures

Measure:Objective response rate (ORR = complete response [CR] + partial [PR])
Time Frame:Up to 2 years
Safety Issue:
Description:Anti-tumor activity of the combination of copanlisib and olaparib, and of the triplet combination of copanlisib, olaparib, and durvalumab will be measured by ORR. Will estimate ORR with 95% confidence intervals (CI).
Measure:Duration of response
Time Frame:From time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years
Safety Issue:
Description:Will use the Kaplan-Meier method to estimate this distribution.
Measure:Progression-free survival
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will use the Kaplan-Meier method to estimate this distribution.
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Will use the Kaplan-Meier method to estimate this distribution.
Measure:Immune-modulatory changes
Time Frame:Baseline up to 2 years
Safety Issue:
Description:Will assess immuno-modulatory changes of copanlisib and olaparib, and of the triplet combination of copanlisib, olaparib and durvalumab using paired t-tests or Wilcoxon signed rank tests.
Measure:PI3K pathway signaling marker levels
Time Frame:Up to 2 years
Safety Issue:
Description:Will assess associations between marker levels (e.g. phosphorylated Akt [pAkt], pS6, p4EBP1) and response using receiver operating characteristic curve analysis, graphical analysis, and logistic regression analysis as appropriate.
Measure:Single nucleotide variation profile
Time Frame:Up to 2 years
Safety Issue:
Description:Will assess associations between marker levels and response using receiver operating characteristic curve analysis, graphical analysis, and logistic regression analysis as appropriate.
Measure:Copy number variation profile
Time Frame:Up to 2 years
Safety Issue:
Description:Will assess associations between marker levels and response using receiver operating characteristic curve analysis, graphical analysis, and logistic regression analysis as appropriate.
Measure:Copanlisib pharmacokinetics
Time Frame:Cycle 1, day 1 and 15: baseline, 30 minutes 1 hour (h), 2h, 3h, and 5h after completion of copanlisib infusion
Safety Issue:
Description:Will assess associations between marker levels and response using receiver operating characteristic curve analysis, graphical analysis, and logistic regression analysis as appropriate.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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