A Study Using Olaparib Tablets for Subjects With Advanced Solid Tumours.

NCT03553108 | Completed Phase 1

• 1 other identifier: D0816C00024
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 3

Brief Summary

This is a phase 1 open label, 4 treatment, 4 sequence and 4 period crossover study in subjects with solid tumours no longer responding to, or eligible for standard therapies, and for whom there are no additional standard therapies likely to benefit the subject.

Conditions

Malignant Solid Tumor

Keywords

Solid Tumor

Outcome Measures

Primary Outcomes (2)

• %PECmax

  Percent prediction error for Cmax

  0 to 72 hours

• %PEAUC

  Percent prediction error for AUC

  0 to 72 hours

Secondary Outcomes (8)

• Maximum plasma concentration (Cmax) obtained directly from the observed concentration versus time data.

  Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.

• Time to maximum plasma concentration (tmax) obtained directly from the observed concentration versus time data.

  Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.

• Area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(0-t)) calculated by linear up/log down trapezoidal summation.

  Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.

• Area under the plasma concentration time curve from zero (pre-dose) extrapolated to infinity (AUC)

  Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.

• Apparent plasma clearance (CL/F).

  Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.

Study Arms (4)

Olaparib Treatment Sequence ABCD

EXPERIMENTAL

On Day 1 of each period, patients will receive a single dose of either Tablet A, B, C, or D, according to the randomization schedule. Serial blood samples for determination of olaparib in plasma will be collected for 72 hours. A - Olaparib Tablet 25 mg B - Olaparib Tablet 100 mg C - Olaparib Tablet 150 mg D - Olaparib Tablet 250 mg

Drug: Olaparib Treatment A; Drug: Olaparib Treatment B; Drug: Olaparib Treatment C; Drug: Olaparib Treatment D

Olaparib Treatment Sequence BDAC

EXPERIMENTAL

On Day 1 of each period, patients will receive a single dose of either Tablet A, B, C, or D, according to the randomization schedule. Serial blood samples for determination of olaparib in plasma will be collected for 72 hours. B - Olaparib Tablet 100 mg D - Olaparib Tablet 250 mg A - Olaparib Tablet 25 mg C - Olaparib Tablet 150 mg

Drug: Olaparib Treatment A; Drug: Olaparib Treatment B; Drug: Olaparib Treatment C; Drug: Olaparib Treatment D

Olaparib Treatment Sequence CADB

EXPERIMENTAL

On Day 1 of each period, patients will receive a single dose of either Tablet A, B, C, or D, according to the randomization schedule. Serial blood samples for determination of olaparib in plasma will be collected for 72 hours. C - Olaparib Tablet 150 mg A - Olaparib Tablet 25 mg D - Olaparib Tablet 250 mg B - Olaparib Tablet 100 mg

Drug: Olaparib Treatment A; Drug: Olaparib Treatment B; Drug: Olaparib Treatment C; Drug: Olaparib Treatment D

Olaparib Treatment Sequence DCBA

EXPERIMENTAL

On Day 1 of each period, patients will receive a single dose of either Tablet A, B, C, or D, according to the randomization schedule. Serial blood samples for determination of olaparib in plasma will be collected for 72 hours. D - Olaparib Tablet 250 mg C - Olaparib Tablet 150 mg B - Olaparib Tablet 100 mg A - Olaparib Tablet 25 mg

Drug: Olaparib Treatment A; Drug: Olaparib Treatment B; Drug: Olaparib Treatment C; Drug: Olaparib Treatment D

Interventions

Olaparib Treatment A DRUG

Olaparib Tablet 25 mg

Olaparib Treatment Sequence ABCD; Olaparib Treatment Sequence BDAC; Olaparib Treatment Sequence CADB; Olaparib Treatment Sequence DCBA

Olaparib Treatment B DRUG

Olaparib Tablet 100 mg

Olaparib Treatment Sequence ABCD; Olaparib Treatment Sequence BDAC; Olaparib Treatment Sequence CADB; Olaparib Treatment Sequence DCBA

Olaparib Treatment C DRUG

Olaparib Tablet 150 mg

Olaparib Treatment Sequence ABCD; Olaparib Treatment Sequence BDAC; Olaparib Treatment Sequence CADB; Olaparib Treatment Sequence DCBA

Olaparib Treatment D DRUG

Olaparib Tablet 250 mg

Olaparib Treatment Sequence ABCD; Olaparib Treatment Sequence BDAC; Olaparib Treatment Sequence CADB; Olaparib Treatment Sequence DCBA

Eligibility Criteria

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

You may qualify if:

• Provision of informed consent prior to any study specific procedures.
• Female or male subject, aged \> 18 years.
• Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory or resistant to standard therapy for which no suitable effective standard therapy is available and in the opinion of the investigator might benefit from olaparib therapy.
• Subjects must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
• Haemoglobin ≥ 100 g/L with no blood transfusion in the past 28 days.
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
• Platelet count ≥ 100 x 109/L.
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
• Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN.
• Subjects must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test:
• Estimated creatinine clearance =\[(140-age \[years\]) x weight (kg) x 1.2\] (x F)a serum creatinine (μmol/L) a where F=0.85 for females and F=1 for males
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Subjects must have a life expectancy ≥ 16 weeks.
• Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.
• Male subjects must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male subjects should also use a highly effective form of contraception if they are of childbearing potential.

You may not qualify if:

• Subjects is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Previous randomisation in the present study.
• Participation in another clinical study with an investigational product during the last 1 month.
• Any previous treatment with a PARP inhibitor, including olaparib.
• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \> 500 ms, electrolyte disturbances, etc.) or subjects with congenital long QT syndrome.
• Subjects receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
• 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 prior to starting olaparib is 2 weeks.
• Concomitant use of known strong (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 prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) \> grade 2) caused by previous cancer therapy, excluding alopecia.
• Subjects with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
• Subjects with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The subject can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Subjects with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
• Major surgery within 2 weeks of starting study treatment and subjects must have recovered from any effects of any major surgery.
• Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
• Subjects unable to swallow orally administered medication and subjects with gastrointestinal disorders likely to interfere with absorption of the study medication including surgery on the upper GI tract and small bowel, malabsorptive disorders, inflammatory bowel disease, GI motility disorders, chronic diarrhea (more than 3 loose bowel movements per day) chronic constipation (no bowel movement for more than two days), recent (in last week) vomiting.

Sponsors & Collaborators

• AstraZeneca: lead
• Iqvia Pty Ltd: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (3)

Research Site

Leuven, 3000, Belgium

Location

Research Site

Liège, 4000, Belgium

Location

Research Site

Wilrijk, 2610, Belgium

Location

Study Officials

• Kevin Punie

  Universitaire Aiekenhuizen Leuven

  PRINCIPAL INVESTIGATOR

• Luc Dirix

  GZA Ziekenhuizen

  PRINCIPAL INVESTIGATOR

• Guy Jerusalem

  Centre Hospitalier Universitaire de Liege

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: Protocol designed to evaluate one or more interventions for treating a disease, syndrome or condition

Study Record Dates

• First Submitted: May 14, 2018
• First Posted: June 12, 2018
• Study Start: May 16, 2018
• Primary Completion: March 12, 2019
• Study Completion: July 1, 2020
• Last Updated: October 1, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

BE (3)