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A Phase 1, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD2014 Administered to Japanese Patients With Advanced Solid Malignancies

A Phase 1, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD2014 Administered to Japanese Patients With Advanced Solid Malignancies

27

The safety analysis set consisted of all patients who received at least 1 dose of AZD2014. [Reporting Groups] - Cohort 1 - AZD2014 50 mg Patients received a single dose of 50 mg AZD2014 on Day 1. After 48 hours' washout, patients received 50 mg AZD2014 BD for 21 days (Cycle 1). Subsequent cycles consisted of 28 days continuous twice daily (BD) dosing. - Cohort 2 - AZD2014 125 mg Patients received a single dose of 125 mg AZD2014 on Day 1. After 48 hours' washout, patients received intermittent weekly 125 mg AZD2014 BD dosing on Day 1 and Day 2 of the week for 21 days (Cycle 1). Subsequent cycles consisted of 28 days intermittent weekly BD dosing. - Cohort 3-1 - AZD2014 25 mg + Paclitaxel Patients received 25 mg AZD2014 BD intermittent weekly dosing (3 days on and 4 days off) combined with intravenous paclitaxel (80 mg/m^2, weekly) for 6 weeks. Paclitaxel was administered on the first day of each week. During the first week, AZD2014 was administered on Days 3, 4 and 5 for PK sampling. - Cohort 3-2 - AZD2014 50 mg + Paclitaxel Patients received 50 mg AZD2014 BD intermittent weekly dosing (3 days on and 4 days off) combined with intravenous paclitaxel (80 mg/m^2, weekly) for 6 weeks. Paclitaxel was administered on the first day of each week. During the first week, AZD2014 was administered on Days 3, 4 and 5 for PK sampling. [Baseline Measures] - Cohort 1 - AZD2014 50 mg Number of Participants [units: Participants] 7 Age Continuous [units: Years] Mean +- Standard Deviation 55.4 +- 14.9 Sex: Female, Male [units: Participants] Female 6, Male 1 Race (NIH/OMB) [units: Participants] American Indian or Alaska Native 0, Asian 7, Native Hawaiian or Other Pacific Islander 0, Black or African American 0, White 0, More than one race 0, Unknown or Not Reported 0 Ethnicity (NIH/OMB) [units: Participants] Hispanic or Latino 0, Not Hispanic or Latino 7, Unknown or Not Reported 0 - Cohort 2 - AZD2014 125 mg Number of Participants [units: Participants] 7 Age Continuous [units: Years] Mean +- Standard Deviation 55.3 +- 11.4 Sex: Female, Male [units: Participants] Female 5, Male 2 Race (NIH/OMB) [units: Participants] American Indian or Alaska Native 0, Asian 7, Native Hawaiian or Other Pacific Islander 0,Black or African American 0, White 0, More than one race 0, Unknown or Not Reported 0 Ethnicity (NIH/OMB) [units: Participants] Hispanic or Latino 0, Not Hispanic or Latino 7, Unknown or Not Reported 0 - Cohort 3-1 - AZD2014 25 mg + Paclitaxel Number of Participants [units: Participants] 6 Age Continuous [units: Years] Mean +- Standard Deviation 59.8 +- 10.7 Sex: Female, Male [units: Participants] Female 3, Male 3 Race (NIH/OMB) [units: Participants] American Indian or Alaska Native 0, Asian 6, Native Hawaiian or Other Pacific Islander 0, Black or African American 0, White 0, More than one race 0, Unknown or Not Reported 0 Ethnicity (NIH/OMB) [units: Participants] Hispanic or Latino 0, Not Hispanic or Latino 6, Unknown or Not Reported 0 - Cohort 3-2 - AZD2014 50 mg + Paclitaxel Number of Participants [units: Participants] 7 Age Continuous [units: Years] Mean +- Standard Deviation 57.9 +- 6.0 Sex: Female, Male [units: Participants] Female 4, Male 3 Race (NIH/OMB) [units: Participants] American Indian or Alaska Native 0, Asian 7, Native Hawaiian or Other Pacific Islander 0, Black or African American 0, White 0, More than one race 0, Unknown or Not Reported 0 Ethnicity (NIH/OMB) [units: Participants] Hispanic or Latino 0, Not Hispanic or Latino 7, Unknown or Not Reported 0 - Total Number of Participants [units: Participants] 27 Age Continuous [units: Years] Mean +- Standard Deviation 57.0 +- 10.7 Sex: Female, Male [units: Participants] Female 18, Male 9 Race (NIH/OMB) [units: Participants] American Indian or Alaska Native 0, Asian 27, Native Hawaiian or Other Pacific Islander 0, Black or African American 0, White 0, More than one race 0, Unknown or Not Reported 0 Ethnicity (NIH/OMB) [units: Participants] Hispanic or Latino 0, Not Hispanic or Latino 27, Unknown or Not Reported 0

[Recruitment Details] Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations 30 adult Japanese patients with advanced solid malignancies were recruited into this open-label, multicentre study form March 2015, and 27 received study treatment. At the time of data cut-off in February 2018, 23 patients had completed the study and 1 patient was still ongoing. [Pre-Assignment Details] Significant events and approaches for the overall study following participant enrollment, but prior to group assignment 33 patients were screened, 30 patients were allocated in the study and 27 received study treatment in 4 different cohorts. [Participant Flow: Overall Study] - Cohort 1 - AZD2014 50 mg STARTED 9, Received study treatment 7, COMPLETED 7, NOT COMPLETED 2, Ongoing at data cut-off 0, Did not receive treatment 2, Lost to Follow-up 0, Condition under investigation worsened 0 - Cohort 2 - AZD2014 125 mg STARTED 7, Received study treatment 7, COMPLETED 6, NOT COMPLETED 1, Ongoing at data cut-off 1, Did not receive treatment 0, Lost to Follow-up 0, Condition under investigation worsened 0 - Cohort 3-1 - AZD2014 25 mg + Paclitaxel STARTED 6, Received study treatment 6, COMPLETED 5, NOT COMPLETED 1, Ongoing at data cut-off 0, Did not receive treatment 0, Lost to Follow-up 0, Condition under investigation worsened 1 - Cohort 3-2 - AZD2014 50 mg + Paclitaxel STARTED 8, Received study treatment 7, COMPLETED 5, NOT COMPLETED 3, Ongoing at data cut-off 0, Did not receive treatment 1, Lost to Follow-up 1, Condition under investigation worsened 1

[Time Frame] From first dose of study treatment up to and including 30 days after the last dose of study treatment (approximately 23 months). [Additional Description] Treatment emergent AEs are presented for the safety analysis set which consisted of all patients who received at least 1 dose of AZD2014. - Cohort 1 - AZD2014 50 mg Total, serious adverse events: 3 participants / 7 participants (42.86%) Total, other (not including serious) adverse events: 7 participants / 7 participants (100.00%) - Cohort 2 - AZD2014 125 mg Total, serious adverse events: 4 participants / 7 participants (57.14%) Total, other (not including serious) adverse events: 7 participants / 7 participants (100.00%) - Cohort 3-1 - AZD2014 25 mg + Paclitaxel Total, serious adverse events: 1 participants / 6 participants (16.67%) Total, other (not including serious) adverse events: 6 participants / 6 participants (100.00%) - Cohort 3-2 - AZD2014 50 mg + Paclitaxel Total, serious adverse events: 0 participants / 7 participants (0.00%) Total, other (not including serious) adverse events: 7 participants / 7 participants (100.00%)

[Summary of safety results] - No AEs with outcome of death were reported. - No other significant AEs were reported. - There were no clinically significant results in haematology, clinical chemistry, and vital signs or ECG during the study. All the patients in the safety analysis set reported at least 1 AE during the study. A total of 26 (96.3%) patients had at least 1 AE considered by the Investigator to be causally related to the study treatment. - Adverse events of Common Terminology Criteria for Adverse Events (CTCAE) Grade or more 3 were reported by at least 11 (40.7%) patients of whom at least 8 (29.6%) patients had AEs of CTCAE Grade or more 3 that were considered by the Investigator to be causally related to the study treatment. - The most commonly reported AE of CTCAE Grade or more 3 by preferred term that was considered by the Investigator to be causally related to the study treatment was neutrophil count decreased, 6 (22.2%) patients. - One (14.3%) patient was still ongoing treatment in Cohort 2 at the time of data cut-off.

[Summary of efficacy results] - A confirmed best objective response of PR was reported for 1 (14.3%) patient in Cohort 2 and 1 (16.7%) patient in Cohort 3-1. - In Cohort 1, 2 patients achieved stable disease for or more 8 weeks, all other cohorts had patients with stable disease for or more7 weeks. [Summary of pharmacokinetic results] - The single dose PK data showed that AZD2014 was rapidly absorbed with median tmax between 0.5 hour and 1.5 hours. A slower absorption was observed in a few patients with individual tmax that ranged from 0.5 hours to 4.0 hours. - After achieving maximum concentration, AZD2014 plasma concentrations appeared to decline rapidly with mean t1/2 between 1.8 hours to 4.1 hours (individual range 1.2 hours to 6.4 hours). - The single dose AZD2014 PK data was not predictive of the steady state kinetics and there was a greater than expected accumulation of drug following multiple dosing with an average RAC value of 3.8 (individual values ranging from 2.0 to 6.0) compared to the average RAC of just over 1.0 that was predicted from the single dose t1/2 values. - An average Tc value of 3.7 (individual values ranging from 2.0 to 5.7) was higher than the Tc average of 1.0 expected, when there were no time-dependent effects. In Cohort 2, the average t1/2 after the LWD was 5.75 hours (individual values ranging from 3.07 hours to 9.40 hours). - Co-administration of AZD2014 and paclitaxel resulted in an apparent delay and/or reduction of AZD2014 absorption although paclitaxel PK were almost unchanged. As paclitaxel is co-administered with ranitidine, diphenhydramine and dexamethasone to reduce infusion reactions and other side effects it is possible one or more of these co-medications are responsible for or contribute to the apparent effect on AZD2014 absorption. - Considering this and the limited number of patients, however, it would be necessary to conduct further investigation to conclude on the drug interaction between AZD2014 and paclitaxel.

Conclusion(s) [Safety] - Overall AZD2014 was well tolerated. - Found safe at continuous and intermittent dosing when combined with paclitaxel. - AZD2014 was well tolerated in Japanese patients both as a single agent and in combination with paclitaxel.

April. 11, 2025

Yes

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Hibi Kazushige

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

RD-clinical-information-Japan@astrazeneca.com

Hibi Kazushige

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

+81-6-4802-3533

RD-clinical-information-Japan@astrazeneca.com

completed

Mar. 17, 2015

Interventional

Safety Study, Single Group Assignment, Open Label

treatment purpose

1

-Histological or cytological confirmation of a solid, malignant tumour that is refractory to standard therapies or for which no standard therapies exist

-For Cohort 3-1 and 3-2, followed as,
Histological or cytological confirmation of a solid, malignant tumour that is refractory to standard therapies or for which no standard therapies exist or where treatment with paclitaxel is an appropriate treatment option. SqNSCLC patients are excluded from the Cohort 3-2.

-World Health Organisation (WHO) performance status (PS) 0-1 with no deterioration over the previous 2 weeks prior to informed consent and minimum life expectancy of 12 weeks

-At least one lesion that can be accurately assessed at baseline by computed tomography (CT) magnetic resonance imaging (MRI) or plain X-ray and is suitable for repeated assessment

-Prior chemotherapy, biological therapy, radiation therapy, antiandrogens, other anticancer therapies including immunotherapy and any investigational agents within 21 days of starting study treatment (not including palliative radiotherapy at focal sites), or corticosteroids within 14 days of starting study treatment.

-Major surgery within 4 weeks prior to the study treatment (excluding placement of vascular access), or minor surgery within 2 weeks prior to the study treatment

-Potent or moderate inhibitors or inducers of cytochrome (CYP) 3A4/5 if taken within the stated washout periods:

-Potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods:

-Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters P-gp (MDR1), Breast cancer resistance protein (BCRP), Organic anion transporting polypeptide (OATP)1B1, OATP1B3, Organic cation transporter (OCT)1 and OCT2 within the appropriate wash-out period (at least 5 x reported terminal elimination half-life (t1/2) of each drug) before the study treatment.

-Any haemopoietic growth factors (eg, granulocyte-colony stimulating factor [G-CSF]) within 2 weeks prior to receiving study drug

-Previous initiation of treatment with AZD2014 in the present study or prior treatment with AZD8055

-With the exception of alopecia, any unresolved toxicities from prior chemotherapy greater than Common toxicity criteria for adverse events (CTCAE) grade 1 at the time of starting study treatment

-Spinal cord or brain metastases unless asymptomatic and stable off steroids for at least 4 weeks prior to start of study treatment

-Subjects with interstitial lung disease as a complication or a history

Both

Advanced Solid Malignancies

investigational material(s)
Generic name etc : AZD2014
INN of investigational material :
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : AZD2014 50mg, 125mg, 25mg and 50mg intermittent BD

Outcome Measure: Safety and tolerability measured by adverse events
Measure Description: This will be assessed in terms of Adverse Events (AEs), laboratory data, vital signs, ECG and physical exams
Time Frame: 6 months in average

+81-3-3542-2511

Mar. 17, 2015