AZD5153 in Patients With Relapsed or Refractory Solid Tumors, Including Lymphomas

Phase 1

Completed

• Conditions: Malignant Solid Tumors; Lymphoma; Ovarian Cancer; Prostate Cancer; Breast Cancer; Pancreatic Cancer
• Interventions: Drug: AZD5153; Drug: Olaparib

• Registration Number: NCT03205176
• Lead Sponsor: AstraZeneca

Brief Summary

This is a first-time-in-man (FTIM) multicenter, dose escalation study designed to investigate the safety, pharmacokinetics, and pharmacodynamics of AZD5153 in patients with malignant solid tumors, including lymphomas.

Detailed Description

The trial will be conducted in two parts, dose escalation and dose expansion. AZD5153 will be investigated as a monotherapy and in combination with olaparib.

AZD5153 monotherapy (dose escalation):

This part of the study will enroll patients with advanced solid malignancies, including lymphoma, and test safety and tolerability of AZD5153 administered as a monotherapy. The dose escalation will proceed by two-fold increments or through lower doses suggested by the CRM until an MTD as defined by dose-limiting toxicity is reached.

Single daily (QD) and twice daily (BID) dosing schedules will be explored in the monotherapy cohort. Additional dose levels or dosing schedules may be evaluated and recommended by study Safety Review Committee (SRC) based on the emerging PK and safety data.

When the AZD5153 monotherapy MTD is established, an expansion cohort consisting of up to 12 additional evaluable patients may be enrolled to confirm the safety and tolerability of the MTD. The dose expansion will be initiated and will enroll patients with histologically or cytologically confirmed platinum resistant or platinum-refractory high grade serous ovarian (HGSO) cancer.

Mandatory tumor biopsies at screening for ovarian cancer patients will be required for patient enrollment in the MTD dose expansion cohort. Optional on-treatment biopsies will be requested from consenting patients in the ovarian expansion cohort.

AZD5153 + olaparib combination:

Dose escalation of AZD5153 in combination with olaparib will also be investigated while the AZD5153 monotherapy dose escalation is ongoing and prior to determination of a monotherapy MTD.

The starting dose of AZD5153 in combination with olaparib will be a dose that has been shown to be safe and tolerated in monotherapy and has been chosen because clinical exposure achieved at this dose is equivalent to preclinical exposure causing tumour growth inhibition in animal models. If the starting dose in combination with olaparib is safe and tolerated, the dose of AZD5153 will be escalated, using the same method as for the monotherapy part of the study, keeping the olaparib dose fixed at 300 mg BID. Intermittent schedules as well as continuous BID or QD dosing of AZD5153 in combination with 300 mg BID olaparib might be tested until a safe and tolerated combination dose and schedule is determined. However, the total dose per cycle of AZD5153 used in combination with olaparib won't exceed the total dose per cycle that has been shown to be safe and tolerated as a monotherapy, and won't be higher than the dose declared to be the monotherapy MTD. If intermittent dosing is explored then the CRM will consider cumulative dosing rather than daily dosing.

AZD5153 and olaparib will be administered in continuous cycles of 21 days. The combination dose escalation part will run in parallel with the AZD5153 monotherapy part (dose escalation and expansion) and will continue until a safe and tolerated combination dose of the two agents is declared. Mandatory paired tumor biopsies at screening and on-treatment will be required for patients enrolled into the combination dose escalation.

Once a dose and schedule of AZD5153 in combination with olaparib is established, up to 12 additional evaluable patients might be enrolled to confirm the safety and tolerability of the dose and schedule of AZD5153 and olaparib in one or more of the indications where clinical activity is observed. Patients with platinum-resistant or platinum-refractory HGSO cancer, triple negative breast cancer, metastatic castration resistant prostate cancer, or pancreatic ductal adenocarcinoma will be eligible for the expansion cohort.

Study Timeline

• Study First Submitted: 2017-06-23
• Study First Submitted QC: 2017-06-29
• Study Start: 2017-06-30
• Study First Posted: 2017-07-02
• Primary Completion: 2021-03-01
• Study Completion: 2021-04-08
• Status Verified: 2021-05
• Last Update Submitted: 2021-05-05
• Last Update Posted: 2021-05-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 49

Inclusion Criteria

Not provided

Exclusion Criteria

1. Patients who have been treated with most recent chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational drugs within 21 days or 5 half-lives (whichever is shorter) from enrollment.

2. Minimum wash-out period for previous PARPi therapy is at least 14 days or 5 half-lives whichever is shorter, or until toxicity from previous PARPi therapy has fully recovered.

3. Patient received more than 5 prior lines of treatment for an advanced solid tumor (including HGSO cancer, TNBC, mCRPC, or PDAC). Patients with lymphoma will be able to enroll without a restriction in the number of previous therapies received, if they otherwise meet eligibility criteria.

4. Major surgery (excluding placement of vascular access) ≤ 21 days from the beginning of enrollment or minor surgical procedures ≤ 7 days. No waiting is required following implantable port and catheter placement.

5. Patient is unable to swallow oral medications or has a gastrointestinal disorder (e.g., malabsorption) that would jeopardize intestinal absorption of AZD5153 and olaparib.

6. Treatment with any of the following:

   • Patient has had prescription or non-prescription drugs or other products known to be strong or moderate inhibitors/inducers of CYP3A4/5, or CYP3A4/5 sensitive substrates or substrates with a narrow therapeutic range, which cannot be discontinued 2 weeks prior to the first day of dosing and withheld throughout the study until 2 weeks after the last dose of AZD5153 and/or olaparib.
   • Drugs that are sensitive substrates of the transporters P-gp, UGT1A1, BCRP, OATP1B1, OAT3, OCT1, OCT2, MATE1 and MATE2K.
   • Herbal preparations/medications are not allowed throughout the study. These herbal medications include, but are not limited to: St. John's wort, kava, ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients should stop using these herbal medications 14 days prior to the first dose of AZD5153 and/or olaparib.
   • Drugs known to prolong QT interval or induce Torsades de Pointes.

7. Refractory nausea and vomiting, previous significant bowel resection that would preclude adequate absorption of study drug and chronic gastrointestinal disease including active or prior documented inflammatory bowel disease.

8. Patient has a history of tuberculosis.

9. Patients receiving a live attenuated vaccine ≤28 days before the first dose of study drug.

10. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment.

11. A diagnosis of MDS or secondary AML (for olaparib combination dose escalation only)

12. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or other comorbidity that renders the patient unsuitable for participation in the study. Screening for chronic conditions is not required.

13. Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTcF) >450 msec obtained from 3 electrocardiograms (ECGs).
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block.
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.

14. History of hypersensitivity to active or inactive excipients of AZD5153 and/or olaparib or drugs with a similar chemical structure or class to AZD5153 and/or olaparib.

15. Patients with non-Hodgkin lymphoma (NHL) at high risk for developing tumor lysis syndrome are not eligible for the monotherapy dose escalation part of this study.

16. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

17. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
AZD5153 Monotherapy	AZD5153	Patients will be enrolled in cohorts of up to 6 patients each in a dose escalating scheme to determine maximum tolerated dose (MTD). AZD5153 will be taken once per day (QD) or two times per day (BID) for 21 days as an oral capsule. Once the MTD is finalized, patients may be enrolled into an expansion cohort at the MTD.
AZD5153 + Olaparib Combination Therapy	AZD5153	Patients will be enrolled in cohorts of up to 6 patients each in a dose escalating scheme to determine MTD. AZD5153 will be taken as oral capsules BID in combination with 300 mg olaparib BID for 21 days.
AZD5153 + Olaparib Combination Therapy	Olaparib	Patients will be enrolled in cohorts of up to 6 patients each in a dose escalating scheme to determine MTD. AZD5153 will be taken as oral capsules BID in combination with 300 mg olaparib BID for 21 days.

Primary Outcome Measures

Name	Time	Method
Incidence of dose-limiting toxicity (DLT).	From the first dose of study treatment up to last day of cycle 1 (21 days)	DLTs will be determined from monitoring adverse events (AEs), and abnormal laboratory tests (clinical chemistry, hematology, and urinalysis), physical examinations, vital signs (blood pressure and pulse), and electrocardiogram (ECG).

Secondary Outcome Measures

Name	Time	Method
Antitumor activity of AZD5153 in patients by assessing the disease control rate (DCR).	Up to 1 year	Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied.; The preliminary anti-tumor activity of AZD5153 in patients with ovarian carcinoma will be evaluated.
Antitumor activity of AZD5153 in patients by assessing progression free survival (PFS).	Up to 1 year	Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied.
Antitumor activity of AZD5153 in patients by assessing overall response rate (ORR).	Up to 1 year	Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied.; The preliminary anti-tumor activity of AZD5153 in patients with ovarian carcinoma will be evaluated.
Peak plasma concentration (Cmax)	Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.	The concentration of AZD5153 and its co-former in blood and plasma will be determined (Cmax will be derived).
The urine concentration of AZD5153 and its co-former (if appropriate).	Urine will be collected pre-dose (spot sample), and volumetrically from 0-6, 6-12, 12-24 hours on Day 1 and Day 15 of Cycle 1.	Total urine volume will be measured for each interval and urine concentration of AZD5153 will be determined. A sample for the determination of 1β-hydroxy deoxycholic acid will be taken from the total urine collection at each scheduled time interval.
The effect of AZD 5153 on QTc interval.	ECGs will be performed at prespecified time points on Days 1 and 2 and 15 and 16 of Cycle 1.	Triplicate 12-lead ECGs will be taken at screening and at prespecified times on Cycle 1 Days 1 and 2 and Days 15 and 16.
Antitumor activity of AZD5153 in patients by assessing duration of response (DoR).	Up to 1 year	Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied.; The preliminary anti-tumor activity of AZD5153 in patients with ovarian carcinoma will be evaluated.
Area under the plasma concentration versus time curve (AUC).	Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.	The concentration of AZD5153 and its co-former in blood will be determined. Area under the curve is the integral of the concentration-time curve. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration. The area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered.
Time to reach peak plasma concentration (tmax).	Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.	The concentration of AZD5153 and its co-former in blood will be determined. Tmax is the time required after administration for the drug to reach its peak plasma concentration.
Elimination half-lfe (t1/2).	Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.	The concentration of AZD5153 and its co-former in blood will be determined. Elimination half-life (t1/2) is the time required for the concentration of the drug to reach half of its original value.
Volume of distribution (Vd).	Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.	The concentration of AZD5153 and its co-former in blood will be determined. Volume of distribution (Vd) is the apparent volume in which a drug is distributed (i.e., the parameter relating drug concentration to drug amount in the body).
Clearance (CL).	Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.	The concentration of AZD5153 and its co-former in blood will be determined. Clearance (CL) is the volume of plasma cleared of the drug per unit time.

Trial Locations

Locations (1)

Research Site; 🇨🇦 Toronto, CA, Canada