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Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Dose Level 0 (DL0): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200mg PO BID on days 1-28 and onalespib 20 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Dose Level 1 (DL1): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200mg PO BID on days 1-28 and onalespib 40 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Dose Level 2 (DL2): Patients received olaparib 300 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 300 mg PO BID on days 1-28 and onalespib 40 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Dose Level 3 (DL3): Patients received olaparib 300 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 300 mg PO BID on days 1-28 and onalespib 80 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Dose Level 2a (DL2a): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200 mg PO BID on days 1-28 and onalespib 80 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Dose Level 3a (DL3a): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200 mg PO BID on days 1-28 and onalespib 120 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Onalespib

Panagiotis A Konstantinopoulos

This phase I trial studies the side effects and best dose of olaparib and onalespib when given together in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable) or ovarian, fallopian tube, primary peritoneal, or triple-negative breast cancer that has come back (recurrent). Olaparib and onalespib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To establish the maximum tolerated dose (MTDs) of olaparib and onalespib (AT13387) administered in combination in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

I. To identify the dose-limiting toxicity (DLT) and other toxicities associated with olaparib and AT13387 administered in combination as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

II. To determine the recommended phase 2 doses (RP2D) of the combination of olaparib and AT13387.

III. To determine the plasma pharmacokinetics of olaparib and AT13387. IV. To document anti-tumor activity of the combination of olaparib and AT13387 as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and progression free survival (PFS). Although the clinical benefit of \[this/these\] drug(s) 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.

OUTLINE: This is a dose-escalation study.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-7 (cycle 0). Beginning in cycle 1, patients receive olaparib PO BID on days 1-28 and onalespib intravenously (IV) over 1 hour on days 1, 2, 8, 9, 15, and 16. 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 every 3 months for up to 2 years.

Olaparib and Onalespib in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, or Triple-Negative Breast Cancer

A Phase 1 Study of PARP Inhibitor Olaparib and HSP90 Inhibitor AT13387 for Treatment of Advanced Solid Tumors With Expansion in Patients With Recurrent Epithelial Ovarian, Fallopian Tube, Peritoneal Cancer or Recurrent Triple-Negative Breast Cancer

MTD was determined by testing increasing doses of the combination of olaparib PO and onalespib IV within dose escalation cohorts consisting of 3 to 6 evaluable participants. MTD reflects the highest dose combination that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. DLTs were defined based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Enrollment to this study was suspended prior to completion of the dose escalation due to discontinuation of further development of onalespib. A true single MTD therefore could not be determined. The two dose levels included in this outcome measure represent the highest well-tolerated dose combinations (Dose Level 2 \[DL2\]: Olaparib 300 mg PO BID and Onalespib 40 mg/m\^2 IV; and Dose Level 2a \[DL2a\]: Olaparib 200 mg PO BID and Onalespib 80 mg/m\^2 IV).

MTD was determined by testing increasing doses of the combination of olaparib PO and onalespib IV within dose escalation cohorts consisting of 3 to 6 evaluable participants. MTD reflects the highest dose combination that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. DLTs were defined based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

DLTs were based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 and were defined as any grade 3 or 4 non-hematologic toxicity (excluding grade 3: fatigue; diarrhea, constipation, and nausea and/or vomiting controlled with supportive measured within 24 hours; hypophosphatemia; hyponatremia; hypomagnesemia; and rash that resolves to \< grade 3 within \< 5 days), grade 4 neutropenia of \> 7 day duration, febrile neutropenia, grade 4 thrombocytopenia or bleeding associated with grade 3 thrombocytopenia, requirement for repeated blood transfusion within 4-6 weeks, any other grade 4 hematologic toxicity, any study treatment-related death, any grade 3 or 4 event considered to be dose-limiting in the opinion of the investigator, and the inability to take 75% or more of the planned dose for olaparib and 4 out of 6 doses for onalespib within the DLT period due to treatment-related adverse events.

Treatment-related toxicities in this outcome include non-hematologic and hematologic adverse events that were either Grade 3+ or occurred in at least 10% of all treated participants, and were considered at least possibly related to olaparib and/or onalespib. Adverse events were graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.

Responses determined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI, where Objective Response (OR) represents either a Complete Response (CR; disappearance of all target lesions) or a Partial Response (PR; at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum diameters).

Responses determined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI, where Progressive Disease (PD) represents (relative to baseline) at least a 20% increase in the sum of diameters of target lesions, appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. The duration of progression-free status was defined as the interval from the date of enrollment to date of either PD or date of last disease assessment.

National Cancer Institute (NCI)

One patient was enrolled under Dose Level 3, but was erroneously treated at Dose Level 2. This patient was replaced within the dose escalation, but remained on treatment on Dose Level 2 throughout the remainder of trial participation. For the purposes of adverse event reporting, this patient has been included in Dose Level 2.

Cycle 0 Dose: Olaparib 200 mg PO BID; Cycle 1+ Dose: Olaparib 200 mg PO BID, Onalespib 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16

Dose Level 0

Cycle 0 Dose: Olaparib 200 mg PO BID; Cycle 1+ Dose: Olaparib 200 mg PO BID, Onalespib 40 mg/m2 IV on days 1, 2, 8, 9, 15, and 16

Dose Level 1

Cycle 0 Dose: Olaparib 300 mg PO BID; Cycle 1+ Dose: Olaparib 300 mg PO BID, Onalespib 40 mg/m2 IV on days 1, 2, 8, 9, 15, and 16

Dose Level 2

Cycle 0 Dose: Olaparib 300 mg PO BID; Cycle 1+ Dose: Olaparib 300 mg PO BID, Onalespib 80 mg/m2 IV on days 1, 2, 8, 9, 15, and 16

Dose Level 3

Cycle 0 Dose: Olaparib 200 mg PO BID; Cycle 1+ Dose: Olaparib 200 mg PO BID, Onalespib 80 mg/m2 IV on days 1, 2, 8, 9, 15, and 16

Dose Level 2a

Cycle 0 Dose: Olaparib 200 mg PO BID; Cycle 1+ Dose: Olaparib 200 mg PO BID, Onalespib 120 mg/m2 IV on days 1, 2, 8, 9, 15, and 16

Dose Level 3a

Dose Level 0: Olaparib 200 mg and Onalespib 20 mg/m^2

Dose Level 1: Olaparib 200 mg and Onalespib 40 mg/m^2

Dose Level 2: Olaparib 300 mg and Onalespib 40 mg/m^2

Dose Level 3: Olaparib 300 mg and Onalespib 80 mg/m^2

Dose Level 2a: Olaparib 200 mg and Onalespib 80 mg/m^2

Dose Level 3a: Olaparib 200 mg and Onalespib 120 mg/m^2

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

ECOG Performance Status

Primary Site of Disease

Measure Description: Staging was based on the FIGO (International Federation of Gynecology and Obstetrics) and AJCC (American Joint Committee on Cancer) systems. Stage I cancers usually have not grown deeply into nearby tissues. Stage II and III cancers have grown more deeply into nearby tissue and may have spread to lymph nodes. Stage IV cancers have spread to other organs or parts of the body. Higher stages are typically associated with worse outcomes.

Stage at Diagnosis

Histology

Lines of Prior Therapy

Dr. Panagiotis Konstantinopoulos

Dose Level 2 Olaparib PO BID

Dose Level 2a Olaparib PO BID

All participants who received at least 75% of planned olaparib and at least 4 doses of onalespib within the DLT period.

All Evaluable Participants

Seven of the 28 patients were not evaluable for DLT assessment and were replaced.

Maximum Tolerated Dose (MTD) of Olaparib Administered in Combination With Onalespib

Dose Level 2 Onalespib IV on Days 1, 2, 8, 9, 15, and 16

Dose Level 2a Onalespib IV on Days 1, 2, 8, 9, 15, and 16

Maximum Tolerated Dose (MTD) of Onalespib Administered in Combination With Olaparib

Dose Level 3: Olaparib 300 mg and Onalespib 80 mg/m^

Patients were considered not evaluable for the DLT outcome if they did not receive at least 75% of the planned olaparib doses or at least 4 doses of onalespib for reasons other than toxicity or DLT. Dose Level 3a did not complete evaluation as enrollment was suspended due to discontinuation of further development of onalespib.

Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)

Diarrhea : Maximum Grade 1-2

Diarrhea : Maximum Grade 3

Nausea : Maximum Grade 1-2

Nausea : Maximum Grade 3

Anemia : Maximum Grade 1-2

Anemia : Maximum Grade 3

Thrombocytopenia/platelet count decrease : Maximum Grade 1-2

Thrombocytopenia/platelet count decrease : Maximum Grade 3

Fatigue : Maximum Grade 1-2

Vomiting : Maximum Grade 1-2

Vomiting : Maximum Grade 3

Abdominal pain : Maximum Grade 1-2

Abdominal pain : Maximum Grade 3

Anorexia : Maximum Grade 1-2

Neutrophil count decreased : Maximum Grade 1-2

Neutrophil count decreased : Maximum Grade 4

Lymphocyte count decreased : Maximum Grade 1-2

Lymphocyte count decreased : Maximum Grade 3

Floaters : Maximum Grade 1-2

Dysgeusia : Maximum Grade 1-2

Number of Participants Who Experienced Treatment-Related Toxicities

Only participants who had their disease re-evaluated via CT or MRI were considered evaluable for response. Six of the 28 participants were taken off study therapy prior to their first on-study disease evaluation.

Spots Global Cancer Trial Database for unresectable high grade fallopian tube serous adenocarcinoma