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

NCT03205176 | Completed Phase 1 FDA Drug

• 2 other identifiers: D6520C00001REFMAL 495
• Study Type: interventional
• Target: 49
• Locations: 2 countries
• Sites: 4

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.

Conditions

Malignant Solid Tumors; Lymphoma; Ovarian Cancer; Breast Cancer; Pancreatic Cancer; Prostate Cancer

Keywords

AZD5153; Olaparib; Malignant solid tumors; Lymphoma; Ovarian Cancer; BRD4; Triple negative breast cancer; Pancreatic cancer; Prostate cancer

Outcome Measures

Primary Outcomes (1)

• Incidence of dose-limiting toxicity (DLT).

  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).

  From the first dose of study treatment up to last day of cycle 1 (21 days)

Secondary Outcomes (12)

• 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 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.

• 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.

• Antitumor activity of AZD5153 in patients by assessing the disease control rate (DCR).

  Up to 1 year

• Antitumor activity of AZD5153 in patients by assessing progression free survival (PFS).

  Up to 1 year

Study Arms (2)

AZD5153 Monotherapy

EXPERIMENTAL

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.

Drug: AZD5153

AZD5153 + Olaparib Combination Therapy

EXPERIMENTAL

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.

Drug: AZD5153; Drug: Olaparib

Interventions

AZD5153 DRUG

AZD5153 is to be taken as oral capsules once or twice per day each day in 21 day cycles. Dosing will continue until disease progression or other study discontinuation criteria are met.

AZD5153 + Olaparib Combination Therapy; AZD5153 Monotherapy

Olaparib DRUG

Olaparib, 300 mg, will be taken BID as oral capsules.

Also known as: Lynparza

AZD5153 + Olaparib Combination Therapy

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must be able to understand the nature of the study and provide a signed and dated, written informed consent prior to any study specific procedures, sampling or analyses.
• Patients should have the ability and willingness to comply with the study and follow-up procedures.
• Patients must have a solid tumor that is refractory to or intolerant of existing therapies known to provide clinical benefit for their clinical condition.
• Age ≥ 18
• Adequate organ function, determined by:
• Absolute neutrophil count (ANC) ≥ 1.5 X 10\^9/L
• Platelets ≥ 100 X 10\^9/L
• Hemoglobin ≥ 9 g/dL
• aPTT ≤1.5 x ULN
• Total bilirubin ≤ 1.5 mg/dL
• ALT and AST ≤ 2.5 x ULN if no liver involvement or ≤ 5 x ULN with liver involvement
• Creatinine \<1.5 times ULN concurrent with creatinine clearance \>50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is \>1.5 times ULN
• Normotensive or well controlled blood pressure (BP) (\<140/90), with or without current antihypertensive treatment. If there is a diagnosis or history of hypertension, patient must have adequately controlled BP on a maximum of 2 antihypertensive medications, as demonstrated by 2 BP measurements taken in the clinical setting by a medical professional within 1 week prior to enrollment. It is strongly recommended that patients who are on antihypertensive medications be followed by a cardiologist or a primary care physician for management of BP while on the study. Patients on a hypertensive medication must be willing and able to check and record twice daily BP readings for a minimum of 3 weeks.
• ECOG performance status of 0-1
• Life expectancy ≥ 3 months

You may not qualify if:

• 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.
• 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.
• 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.
• 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.
• Patient is unable to swallow oral medications or has a gastrointestinal disorder (e.g., malabsorption) that would jeopardize intestinal absorption of AZD5153 and olaparib.
• 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.
• 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.
• Patient has a history of tuberculosis.
• Patients receiving a live attenuated vaccine ≤28 days before the first dose of study drug.
• 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.
• A diagnosis of MDS or secondary AML (for olaparib combination dose escalation only)

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (4)

Research Site

Sarasota, Florida, 34232, United States

Location

Research Site

Oklahoma City, Oklahoma, 73104, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Research Site

Toronto, CA, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Lymphoma; Ovarian Neoplasms; Breast Neoplasms; Pancreatic Neoplasms; Prostatic Neoplasms; Triple Negative Breast Neoplasms

Interventions

AZD5153; olaparib

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Digestive System Neoplasms; Digestive System Diseases; Pancreatic Diseases; Genital Neoplasms, Male; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Erika P Hamilton, MD

  Sarah Cannon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 23, 2017
• First Posted: July 2, 2017
• Study Start: June 30, 2017
• Primary Completion: March 1, 2021
• Study Completion: April 8, 2021
• Last Updated: May 6, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

CA (1); US (3)