Investigate the Safety and Tolerability of Olaparib Tablet in Japanese Patients With Advanced Solid Malignancies

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01813474
• Collaborator: (none)
• Enrollment: 23
• Locations: 3
• Arm: 1
• Actual Duration (Months): 41.2
• Patients Per Site: 7.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The objective of this study will be to investigate the safety and tolerability of olaparib tablet when given orally to Japanese patients with advanced solid malignancies. In addition, the pharmacokinetic profile, MTD (if possible) and efficacy of olaparib will be investigated.

Condition or Disease	Intervention/Treatment	Phase
Cancer; Advanced Solid Malignancies	Drug: olaparib	Phase 1

Detailed Description

MTD - maximum tolerated dose

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I, Open-label Study to Assess the Safety and Tolerability of Doses of Olaparib Tablet in Japanese Patients With Advanced Solid Malignancies
• Actual Study Start Date: Mar 25, 2013
• Actual Primary Completion Date: Aug 31, 2016
• Actual Study Completion Date: Aug 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: olaparib tablet monotherapy olaparib tablet	Drug: olaparib; tablet oral

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [From the start dose to 30 days after the last dose of study drug]

   An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. This was recorded if it happend from the start dose to 30 days after the last of study drug.

Secondary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities [From the start dose to 28 days after the first dose of study drug]

   Dose Limiting Toxicities were defined as study specific events that is determined to be possibly or probably related to olaparib (as determined by the investigator) and occurring during the first cycle of treatment (28 days after the first dose), irrespective of whether the toxicity resolved.

2. Cmax Following Single Dosing [Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose]

3. Cmax Following Multiple Dosing [Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose]

4. Tmax Following Single Dosing [Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose]

5. Tmax Following Multiple Dosing [Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose]

6. AUC Following Single Dosing [Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose]

7. AUC at Steady State Following Multiple Dosing [Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists.

• Subjects who have overall good overall general condition.

• Subjects who agree to hospitalisation from starting olaparib to multiple dose period at day 15.

• Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status.

• Subjects who have at least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI at baseline and follow up visits

Exclusion Criteria:

• Subjects who received any previous treatment with a PARP (poly adenosine diphosphate-ribose polymerase) inhibitor, including olaparib.

• Subjects receiving inhibitors of CYP3A4 (cytochrome P450 3A4).

• Subjects with symptomatic uncontrolled brain metastases.

• Subjects with myelodysplastic syndrome/acute myeloid leukaemia.

• Subjects with a known hypersensitivity to olaparib or any of the excipients of the product.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Chuo-ku		Japan	104-0045
2	Research Site	Fukuoka-shi		Japan	811-1395
3	Research Site	Sapporo-shi		Japan	003-0804

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Thomas Morris, M.D., Global Medicines Development

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• D081BC00001_Study_Report_Synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01813474
• Other Study ID Numbers: D081BC00001
• First Posted: Mar 19, 2013
• Last Update Posted: Jan 16, 2018
• Last Verified: Dec 1, 2017

• Keywords provided by AstraZeneca: Cancer; Tumour; Solid Malignancies
• Additional relevant MeSH terms: Neoplasms; Olaparib

Study Results

Participant Flow

Recruitment Details	First patient enrolled on 25 March 2013. Last patient enrolled on 31 October 2013. Data cut off on 31 July 2014.
Pre-assignment Detail	A total of 28 participants gave informed consent to join this study. Five participants were screen failures so that 23 participants were assigned and received study treatment

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part	300 mg Bid, Expansion Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part	Olaparib tablet 300 mg bid, 600 mg/day, expansion part
Period Title: Overall Study
STARTED	4	7	12
COMPLETED	1	0	1
NOT COMPLETED	3	7	11

Baseline Characteristics

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part	300 mg Bid, Expansion Part	Total
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part	Olaparib tablet 300 mg bid, 600 mg/day, expansion part	Total of all reporting groups
Overall Participants	4	7	12	23
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	42.0 (8.68)	55.4 (8.98)	57.3 (12.43)	54.1 (11.94)
Sex: Female, Male (Count of Participants)
Female	4 100%	4 57.1%	7 58.3%	15 65.2%
Male	0 0%	3 42.9%	5 41.7%	8 34.8%
Primary tumour location (Count of Participants)
Breast	1 25%	1 14.3%	3 25%	5 21.7%
Colorectal	0 0%	0 0%	1 8.3%	1 4.3%
Lung	0 0%	1 14.3%	2 16.7%	3 13%
Peritoneum	0 0%	0 0%	1 8.3%	1 4.3%
Pancreas	0 0%	1 14.3%	0 0%	1 4.3%
Ovary	0 0%	2 28.6%	2 16.7%	4 17.4%
Uterus	1 25%	1 14.3%	0 0%	2 8.7%
Cervix	2 50%	0 0%	0 0%	2 8.7%
Colon	0 0%	0 0%	1 8.3%	1 4.3%
Gastric Antrum	0 0%	0 0%	1 8.3%	1 4.3%
Other	0 0%	1 14.3%	1 8.3%	2 8.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. This was recorded if it happend from the start dose to 30 days after the last of study drug.
Time Frame	From the start dose to 30 days after the last dose of study drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part	300 mg Bid, Expansion Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part	Olaparib tablet 300 mg bid, 600 mg/day, expansion part
Measure Participants	4	7	12
At least 1 Adverse Events (AE)	4 100%	7 100%	10 83.3%
At least 1 AE of CTCAE Grade 3 or higher	1 25%	3 42.9%	1 8.3%
At least 1 Serious Adverse Events (SAE)	1 25%	0 0%	0 0%

2. Secondary Outcome

Title	Number of Participants With Dose Limiting Toxicities
Description	Dose Limiting Toxicities were defined as study specific events that is determined to be possibly or probably related to olaparib (as determined by the investigator) and occurring during the first cycle of treatment (28 days after the first dose), irrespective of whether the toxicity resolved.
Time Frame	From the start dose to 28 days after the first dose of study drug

Outcome Measure Data

Analysis Population Description

All patients in only the dose escalation part who received olaparib and completed the safety follow-up through the dose-limiting toxicity (DLT) evaluation period (28 days), or who experienced a DLT.

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib tablet 300 mg bid, 600 mg/day, dose escalation part
Measure Participants	3	6
Number [Participants]	0 0%	0 0%

3. Secondary Outcome

Title	Cmax Following Single Dosing
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose

Outcome Measure Data

Analysis Population Description

Dose escalation part only

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part
Measure Participants	4	7
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	6.697 (95.69)	7.743 (34.76)

4. Secondary Outcome

Title	Cmax Following Multiple Dosing
Time Frame	Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose

Outcome Measure Data

Analysis Population Description

Dose escalation part only. Two participants (1 in 200 mg bid and 1 in 300 mg bid) had no PK data due to early discontinuation prior to Day 15.

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part
Measure Participants	3	6
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	7.668 (46.93)	8.434 (35.05)

5. Secondary Outcome

Title	Tmax Following Single Dosing
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose

Outcome Measure Data

Analysis Population Description

Dose escalation part only

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part
Measure Participants	4	7
Median (Full Range) [hour]	2.00 (95.69)	1.98 (34.76)

6. Secondary Outcome

Title	Tmax Following Multiple Dosing
Time Frame	Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose

Outcome Measure Data

Analysis Population Description

Dose escalation part only. Two participants (1 in 200 mg bid and 1 in 300 mg bid) had no PK data due to early discontinuation prior to Day 15.

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part
Measure Participants	3	6
Median (Full Range) [hour]	1.50 (46.93)	3.00 (35.05)

7. Secondary Outcome

Title	AUC Following Single Dosing
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours at post-dose

Outcome Measure Data

Analysis Population Description

Dose escalation part only. One participant in 200 mg bid had no AUC data because AUC was not calculable for this participant.

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part
Measure Participants	3	7
Geometric Mean (Geometric Coefficient of Variation) [μg*h/mL]	61.97 (473.4)	46.21 (64.64)

8. Secondary Outcome

Title	AUC at Steady State Following Multiple Dosing
Time Frame	Day 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours at post-dose

Outcome Measure Data

Analysis Population Description

Dose escalation part only. Two participants (1 in 200 mg bid and 1 in 300 mg bid) had no PK data due to early discontinuation prior to Day 15.

Arm/Group Title	200 mg Bid, Dose Escalation Part	300 mg Bid, Dose Escalation Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part	Olaparib table 300 mg bid, 600 mg/day, dose escalation part
Measure Participants	3	6
Geometric Mean (Geometric Coefficient of Variation) [μg*h/mL]	36.50 (71.94)	52.34 (68.17)

Adverse Events

Time Frame	Through treatment and 30-day follow-up period, an average of about 4 months.
Arm/Group Title	200 mg Bid, Dose Escalation Part		300 mg Bid, Dose Escalation Part		300 mg Bid, Expansion Part
Arm/Group Description	Olaparib tablet 200 mg bid, 400 mg/day, dose escalation part		Olaparib table 300 mg bid, 600 mg/day, dose escalation part		Olaparib tablet 300 mg bid, 600 mg/day, expansion part
All Cause Mortality
	200 mg Bid, Dose Escalation Part		300 mg Bid, Dose Escalation Part		300 mg Bid, Expansion Part
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	200 mg Bid, Dose Escalation Part		300 mg Bid, Dose Escalation Part		300 mg Bid, Expansion Part
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		0/7 (0%)		0/12 (0%)
Gastrointestinal disorders
Ileus	1/4 (25%)	1	0/7 (0%)	0	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	200 mg Bid, Dose Escalation Part		300 mg Bid, Dose Escalation Part		300 mg Bid, Expansion Part
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		7/7 (100%)		10/12 (83.3%)
Blood and lymphatic system disorders
Anaemia	0/4 (0%)		4/7 (57.1%)		2/12 (16.7%)
Neutropenia	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Eye disorders
Erythema of eyelid	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Eye pruritus	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/4 (0%)		1/7 (14.3%)		1/12 (8.3%)
Constipation	0/4 (0%)		2/7 (28.6%)		4/12 (33.3%)
Diarrhoea	0/4 (0%)		2/7 (28.6%)		2/12 (16.7%)
Duodenitis	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Dyspepsia	0/4 (0%)		2/7 (28.6%)		1/12 (8.3%)
Gastritis	0/4 (0%)		0/7 (0%)		1/12 (8.3%)
Nausea	1/4 (25%)		6/7 (85.7%)		3/12 (25%)
Stomatitis	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Toothache	1/4 (25%)		0/7 (0%)		0/12 (0%)
Vomiting	0/4 (0%)		1/7 (14.3%)		1/12 (8.3%)
General disorders
Fatigue	0/4 (0%)		1/7 (14.3%)		2/12 (16.7%)
Malaise	0/4 (0%)		2/7 (28.6%)		2/12 (16.7%)
Oedema	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Pyrexia	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Hepatobiliary disorders
Hepatic function abnormal	0/4 (0%)		0/7 (0%)		1/12 (8.3%)
Infections and infestations
Nasopharyngitis	1/4 (25%)		0/7 (0%)		1/12 (8.3%)
Paronychia	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Pneumonia	0/4 (0%)		0/7 (0%)		1/12 (8.3%)
Pyelonephritis	1/4 (25%)		0/7 (0%)		0/12 (0%)
Upper respiratory tract infection	0/4 (0%)		0/7 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Contusion	0/4 (0%)		0/7 (0%)		1/12 (8.3%)
Procedural pain	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Investigations
Alanine aminotransferase increased	0/4 (0%)		1/7 (14.3%)		1/12 (8.3%)
Aspartate aminotransferase increased	0/4 (0%)		1/7 (14.3%)		1/12 (8.3%)
Blood creatinine increased	0/4 (0%)		1/7 (14.3%)		1/12 (8.3%)
Grip strength decreased	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Lymphocyte count decreased	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Neutrophil count decreased	0/4 (0%)		2/7 (28.6%)		2/12 (16.7%)
Platelet count decreased	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
White blood cell count decreased	0/4 (0%)		3/7 (42.9%)		2/12 (16.7%)
Metabolism and nutrition disorders
Decreased appetite	0/4 (0%)		4/7 (57.1%)		3/12 (25%)
Hypoglycaemia	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)		0/7 (0%)		1/12 (8.3%)
Back pain	1/4 (25%)		0/7 (0%)		0/12 (0%)
Myalgia	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Pain in extremity	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Nervous system disorders
Dizziness	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Dysgeusia	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Headache	1/4 (25%)		0/7 (0%)		0/12 (0%)
Psychiatric disorders
Anxiety	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Renal and urinary disorders
Proteinuria	0/4 (0%)		2/7 (28.6%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Dysaesthesia pharynx	1/4 (25%)		1/7 (14.3%)		0/12 (0%)
Dyspnoea	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Pruritus	0/4 (0%)		1/7 (14.3%)		0/12 (0%)
Rash maculo-papular	0/4 (0%)		0/7 (0%)		1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.