Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Unresectable Malignant Solid Neoplasm
Conditions
Brief summary
This phase Ib trial seeks to identify the side effects and best dose of the combination of copanlisib and olaparib when given together with durvalumab. The trial will evaluate how well the drug combinations work in treating patients with advanced cancers who have solid tumors that have spread from where they first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves and may stop growing. 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. The treatment 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 OBJECTIVE: 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, and explore exposure-response relationships. IV. To correlate molecular alterations with OR (CR+PR). OUTLINE: This is a dose-escalation and expansion study of the doublet combination of copanlisib and olaparib or the triplet combination of copanlisib, olaparib, durvalumab. In the dose escalation phase of the study, patients treated with the doublet combination will receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1 and 15 or days 1, 8, and 15 depending on dose level and olaparib orally (PO) twice daily (BID) on days 1-28 of each cycle. Patients treated with the triplet combination will also receive copanlisib hydrochloride and olaparib, in addition to also receiving durvalumab beginning in cycle 2. Beginning in cycle 2, patients treated with the triplet combination will receive durvalumab IV over 1 hour on day 1 of each cycle. In the dose expansion phase of the study, patients will be treated with the best study drug dose identified in the dose escalation phase of the study. For all patients treated with the doublet and triplet combinations, the cycles will repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples at baseline within 7 days of cycle 1 day 1 (C1D1), days 8 and 15 of cycle 1 and day 15 of subsequent cycles, at time of restaging, and end of treatment/progression. Patients undergo x-ray, computed tomography (CT), and magnetic resonance imaging (MRI) at the end of cycle 2 and then every 8 weeks. Patients also undergo an echocardiography (ECHO) during pre-study within 28 days of C1D1 and tumor biopsy at baseline within 7 days of C1D1 and day 15 of cycle 1 or 2, and may undergo an optional biopsy at end of treatment/progression. After completion of study treatment, all patients are followed up at 30 days and then every 3 months for up to 2 years.
Interventions
PROCEDUREBiopsy Procedure
Undergo tumor biopsy
PROCEDUREBiospecimen Collection
Undergo collection of blood samples
PROCEDUREComputed Tomography
Undergo CT
Given IV
BIOLOGICALDurvalumab
Given IV
PROCEDUREEchocardiography Test
Undergo ECHO
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
DRUGOlaparib
Given PO
PROCEDUREX-Ray Imaging
Undergo x-ray
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ELIGIBILITY CRITERIA FOR ENROLLMENT INTO STEPS 1, 2, AND 3 * Patients must have germline or somatic mutations in DDR genes: BARD1, BRCA1, BRCA2, BRIP1, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D; or actionable mutations in the PTEN gene, or hotspot mutations in the PIK3CA gene (E542, E545 or H1047 are accepted). Local testing in Clinical Laboratory Improvement Act (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 * 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 \>= 3 weeks beyond treatment with any chemotherapy or \>= 4 weeks beyond treatment with 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 * Age \>= 18 years. Because no dosing or adverse event (AE) data are currently available on the use of copanlisib in combination with olaparib +/- durvalumab (MEDI4736) in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials * Patients with a mutation within both the DDR and PTEN/PIK3CA pathways will be assessed by the genomics Precision Oncology Decision Support group at MD Anderson, and the patient will be allocated to the PI3K or DDR expansion group deemed to be the main driver. If the actionability between the groups is deemed to be equivocal, then the patient will be allocated to the expansion cohort with fewer patients * 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 \>= 140,000/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; HIV testing pre-study not required) 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 * Ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) must have a legally authorized representative or caregiver who gives such consent * Patient is willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations * Patients with a tumor that is readily accessible for biopsy * ELIGIBILITY CRITERIA FOR ENROLLMENT INTO STEP 2 AND 3 ONLY * Body weight \> 30 kg * Life expectancy \>= 16 weeks
Exclusion criteria
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | The DLT monitoring time frame was Cycle 1 through Cycle 2 Day 1 for the doublet combination (SIL1, SIL2, SIL3, and SIL3A) , and Cycle 1 through Cycle 3 Day 1 for the triplet combination (S2L1) | A DLT was evaluated according to the NCI CTCAE 5.0. An AE was defined as DLT if it met any of the following events: any grade 5 toxicity; any grade 2 toxicity that require permanent discontinuation of durvalumab or combination therapies within the first 4 weeks; grade 4 neutropenia; febrile neutropenia; neutropenic infection; grade ≥ 3 thrombocytopenia with bleeding; grade 4 thrombocytopenia; Grade 4 anemia; non-hematological grade ≥ 4 toxicities; confirmation of QTc prolongation; grade ≥3 AE hyperglycemia or hypertension lasting \< 7 days; grade 3 skin rash despite optimal medical intervention; grade 3 diarrhea despite optimal medical intervention; any toxicity greater than baseline & clinically significant or unacceptable & disrupts dosing for more than 14 days; any event, including significant dose reductions or omissions as judged by safety review committee; & any toxicity in any course of treatment that in the opinion of the investigators and medical monitors is dose-limiting. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | 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 | Will use the Kaplan-Meier method to estimate this distribution. |
| Progression-free Survival | From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years | Will use the Kaplan-Meier method to estimate this distribution. |
| Objective Response Rate (ORR = Complete Response [CR] + Partial [PR]) | Up to 2 years | 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. |
| Pharmacokinetics of Copanlisib and Olaparib (Doublet Combination); Step 1 Cohorts | Step 1: C1D8- baseline; 30 and 55 mins post start copanlisib(copa),1 hour (h), 3h, 5h, 7h, and 23h after end of copa; C1D15: baseline, 30 min, 55min post start copa infusion. Step 1 DL3A: only C1D15 timepoints. | Assessment of pharmacokinetic profiles of copanlisib and olaparib at various treatment timepoints. |
| Pharmacokinetics Off Copanlisib, Olaparib, and Durvalumab (Triplet Combination); Step 2 Cohorts | Cycle 1, day 15: baseline (predose), 30 min, 55 min post start copanlisib infusion, and 1 h, 3h, 5h, 7h, and 23h post end of copanlisib infusion, Day 1 on cycles 2-5: baseline (predose) and 50 min post start of durvalumab infusion | Assessment of pharmacokinetic profiles of copanlisib, olaparib, and durvalumab at various treatment timepoints. |
| Overall Survival | Up to 2 years | Will use the Kaplan-Meier method to estimate this distribution. |
Countries
United States
Participant flow
Recruitment details
Phase Ib multicenter study led by MD Anderson Cancer Center. Participants were eligible if they had (1) advanced solid tumors for which curative measures did not exist or were no longer effective and (2) an actionable mutation in DNA Damage Response (DDR) genes (BARD1, BRCA1,BRCA2, BRIP1, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D), PTEN, or PIK3CA hotspots (E542, E545, or H1047).
Pre-assignment details
Patients were enrolled into the following cohorts: Step 1 (Copanlisib and Olaparib dose escalation), Step 2 (Copanlisib, Olaparib, and Durvalumab dose escalation), or Step 3 (Copanlisib and Olaparib dose expansion). Patients enrolled in Step 3 were enrolled in the following dose expansion sub-cohorts: (1) those with germline or somatic DDR mutations (the DDR arm) or (2) those with PIK3CA or PTEN mutations (PIK3CA/PTEN arm). Thirty-nine patients were treated in Steps 1 - 3.
Participants by arm
| Arm | Count |
|---|---|
| Step 1 Dose Level 1 Step 1 DL1: Copanlisib 45 mg IV (days 1, 8, 15) + Olaparib 200 mg PO BID; 28-day cycle | 9 |
| Step 1 Dose Level 2 Step 1 DL2: Copanlisib 45 mg IV (days 1, 8, 15) + Olaparib 300 mg PO BID; 28-day cycle | 3 |
| Step 1 Dose Level 3 Step 1 DL3: Copanlisib 60 mg IV (days 1, 8, 15) + Olaparib 300 mg PO BID; 28-day cycle | 10 |
| Step 1 Dose Level 3A Step 1 DL3A: Copanlisib 60 mg IV (days 1 and15) + Olaparib 300 mg PO BID; 28-day cycle | 6 |
| Step 2 Dose Level 1 Step 2 DL1:
Copanlisib 60 mg IV (days 1 and15) + Olaparib 300 mg PO BID + Durvalumab 1500 mg IV on day 1 starting at C2D1 ; 28-day cycle | 4 |
| Step 3 DDR Arm Step 3 DL3A: Copanlisib 60 mg IV (days 1 and15) + Olaparib 300 mg PO BID; 28-day cycle | 2 |
| Step 3 PIK3CA/PTEN Arm Step 3 DL3A: Copanlisib 60 mg IV (days 1 and15) + Olaparib 300 mg PO BID; 28-day cycle | 5 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Progression | 8 | 1 | 7 | 5 | 4 | 2 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 1 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Step 1 Dose Level 2 | Step 1 Dose Level 3 | Step 1 Dose Level 3A | Step 2 Dose Level 1 | Step 3 DDR Arm | Step 3 PIK3CA/PTEN Arm | Step 1 Dose Level 1 | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 8 Participants | 3 Participants | 4 Participants | 2 Participants | 3 Participants | 6 Participants | 27 Participants |
| Age, Continuous | 67 years | 59 years | 63.5 years | 51 years | 44.5 years | 64 years | 63 years | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 8 Participants | 5 Participants | 4 Participants | 2 Participants | 4 Participants | 9 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 4 Participants | 4 Participants | 1 Participants | 5 Participants | 9 Participants | 34 Participants |
| Region of Enrollment United States | 3 participants | 10 participants | 6 participants | 4 participants | 2 participants | 5 participants | 9 participants | 39 participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 6 Participants | 3 Participants | 2 Participants | 2 Participants | 6 Participants | 27 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 3 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 9 | 1 / 3 | 8 / 10 | 2 / 6 | 2 / 4 | 0 / 2 | 2 / 5 |
| other Total, other adverse events | 9 / 9 | 3 / 3 | 10 / 10 | 6 / 6 | 4 / 4 | 2 / 2 | 5 / 5 |
| serious Total, serious adverse events | 5 / 9 | 1 / 3 | 5 / 10 | 5 / 6 | 3 / 4 | 2 / 2 | 5 / 5 |
Outcome results
Primary
Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D)
A DLT was evaluated according to the NCI CTCAE 5.0. An AE was defined as DLT if it met any of the following events: any grade 5 toxicity; any grade 2 toxicity that require permanent discontinuation of durvalumab or combination therapies within the first 4 weeks; grade 4 neutropenia; febrile neutropenia; neutropenic infection; grade ≥ 3 thrombocytopenia with bleeding; grade 4 thrombocytopenia; Grade 4 anemia; non-hematological grade ≥ 4 toxicities; confirmation of QTc prolongation; grade ≥3 AE hyperglycemia or hypertension lasting \< 7 days; grade 3 skin rash despite optimal medical intervention; grade 3 diarrhea despite optimal medical intervention; any toxicity greater than baseline & clinically significant or unacceptable & disrupts dosing for more than 14 days; any event, including significant dose reductions or omissions as judged by safety review committee; & any toxicity in any course of treatment that in the opinion of the investigators and medical monitors is dose-limiting.
Time frame: The DLT monitoring time frame was Cycle 1 through Cycle 2 Day 1 for the doublet combination (SIL1, SIL2, SIL3, and SIL3A) , and Cycle 1 through Cycle 3 Day 1 for the triplet combination (S2L1)
Population: To be evaluable for DLT, patients must receive at least 75% of Olaparib doses and have no missed Copanlisib doses. In Step 1 dose level 3, Step 1 dose level 3A, Step 2 dose level 1, and Step 3 PIK3CA/PTEN arm, 8 patients were not evaluable for DLT because they did not receive sufficient drug in Cycle 1.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Step 1 Dose Level 1 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | Not evaluable for DLT | 0 Participants |
| Step 1 Dose Level 1 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | No DLT | 8 Participants |
| Step 1 Dose Level 1 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | DLT | 1 Participants |
| Step 1 Dose Level 2 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | No DLT | 3 Participants |
| Step 1 Dose Level 2 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | DLT | 0 Participants |
| Step 1 Dose Level 2 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | Not evaluable for DLT | 0 Participants |
| Step 1 Dose Level 3 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | Not evaluable for DLT | 4 Participants |
| Step 1 Dose Level 3 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | DLT | 2 Participants |
| Step 1 Dose Level 3 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | No DLT | 4 Participants |
| Step 1 Dose Level 3A | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | No DLT | 5 Participants |
| Step 1 Dose Level 3A | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | DLT | 0 Participants |
| Step 1 Dose Level 3A | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | Not evaluable for DLT | 1 Participants |
| Step 2 Dose Level 1 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | No DLT | 3 Participants |
| Step 2 Dose Level 1 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | DLT | 0 Participants |
| Step 2 Dose Level 1 | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | Not evaluable for DLT | 1 Participants |
| Step 3 DDR Arm | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | DLT | 0 Participants |
| Step 3 DDR Arm | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | Not evaluable for DLT | 0 Participants |
| Step 3 DDR Arm | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | No DLT | 2 Participants |
| Step 3 PIK3CA/PTEN Arm | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | Not evaluable for DLT | 2 Participants |
| Step 3 PIK3CA/PTEN Arm | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | No DLT | 3 Participants |
| Step 3 PIK3CA/PTEN Arm | Number of Patients With Dose Limiting Toxicities (DLT) as a Measure of Safety Profile to Determine Recommended Phase 2 Dose (RP2D) | DLT | 0 Participants |
Secondary
Duration of Response
Will use the Kaplan-Meier method to estimate this distribution.
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
Secondary
Objective Response Rate (ORR = Complete Response [CR] + Partial [PR])
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.
Time frame: Up to 2 years
Secondary
Overall Survival
Will use the Kaplan-Meier method to estimate this distribution.
Time frame: Up to 2 years
Secondary
Pharmacokinetics of Copanlisib and Olaparib (Doublet Combination); Step 1 Cohorts
Assessment of pharmacokinetic profiles of copanlisib and olaparib at various treatment timepoints.
Time frame: Step 1: C1D8- baseline; 30 and 55 mins post start copanlisib(copa),1 hour (h), 3h, 5h, 7h, and 23h after end of copa; C1D15: baseline, 30 min, 55min post start copa infusion. Step 1 DL3A: only C1D15 timepoints.
Secondary
Pharmacokinetics Off Copanlisib, Olaparib, and Durvalumab (Triplet Combination); Step 2 Cohorts
Assessment of pharmacokinetic profiles of copanlisib, olaparib, and durvalumab at various treatment timepoints.
Time frame: Cycle 1, day 15: baseline (predose), 30 min, 55 min post start copanlisib infusion, and 1 h, 3h, 5h, 7h, and 23h post end of copanlisib infusion, Day 1 on cycles 2-5: baseline (predose) and 50 min post start of durvalumab infusion
Secondary
Progression-free Survival
Will use the Kaplan-Meier method to estimate this distribution.
Time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years