AZD9291 in Combination With Ascending Doses of Novel Therapeutics

• Register: ClinicalTrials.gov
• Last refreshed on: 11 March 2024
• Main ID: NCT02143466
• Date of registration: 09/05/2014
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca
• Public title: AZD9291 in Combination With Ascending Doses of Novel Therapeutics
• Scientific title: A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety,Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm+ Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON).
• Date of first enrolment: August 5, 2014
• Target sample size: 344
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT02143466
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

Canada, China, Japan, Korea, Republic of, Poland, Russian Federation, Taiwan, Ukraine, United States

Contacts

• Name: Pasi A Jänne, MD, PhD
• Affiliation: Dana-Faber Cancer Institute

Key inclusion & exclusion criteria

Inclusion Criteria Signed informed consent Male or female aged at least 18 years and older.
Patients from Japan aged at least 20 years.

Histological or cytological confirmation of EGFRm+ NSCLC. Confirmation that the tumour
harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including exon
19 deletion and L858R). Radiological documentation of disease progression while on a
previous continuous treatment with an EGFR TKI eg, gefitinib or erlotinib. These patients
must have radiological progression (as per site assessment) on the last treatment
administered prior to enrolling in the study.

At least one lesion, not previously irradiated, not biopsied during the screening period,
that can be accurately measured at baseline as =10 mm in the longest diameter (except lymph
nodes which must have short axis =15 mm) with computerised tomography (CT) or magnetic
resonance imaging (MRI) which is suitable for accurate repeated measurements. Adequate
haematological, liver and renal function as well as coagulation parameters.

ECOG/WHO performance status of 0 or 1 or KPS >80. Ability to swallow and retain oral
medications. Prior to study entry, local confirmation of tumour cMET status is acceptable,
a central result will be confirmed retrospectively. Local confirmation of tumour T790M
status is acceptable if performed with an approved test and agreed by AstraZeneca.

Agree to use adequate contraceptive measures.

Exclusion Criteria Treatment with an EGFR TKI within approximately 5x half-life (eg, within
8 days for erlotinib, gefitinib or afatanib, or within 10 days for dacomitinib) of the
first dose of study treatment. Any cytotoxic chemotherapy, investigational agents or other
anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or
clinical study within 14 days of the first dose of study treatment Patients currently
receiving medications or herbal supplements known to be potent inducers of CYP3A4 (at least
3 weeks prior). For AZD6094 patients currently receiving prior to receiving the first dose,
medications known to be strong inhibitors of CYP1A2.

Prior AZD9291 dosing in the present study. Prior treatment with a 3rd generation
(T790M-directed) therapy (eg, AZD9291, rociletinib or HM61713) outside of this study is
permitted if allocated to the 3rd generation EGFR TKI cohort. Prior or current treatment
with AZD6094 or another cMET inhibitor (eg, foretinib, crizotinib, cabozantinib,
onartuzumab) if allocated to AZD9291 plus AZD6094 combination. Radiotherapy with a limited
field of radiation for palliation within 1 week of the first dose of study treatment, with
the exception of patients receiving radiation to more than 30% of the bone marrow or with a
wide field of radiation which must be completed within =4 weeks of the first dose of study
treatment Major surgical procedure, or significant traumatic injury within 4 weeks of the
first dose of study treatment, or have an anticipated need for major surgery during the
study.

Currently receiving treatment with warfarin sodium. LMWH is allowed. Active
gastrointestinal disease or other condition that will interfere significantly with the
absorption, distribution, metabolism, or excretion of oral therapy Any of the following
cardiac diseases currently or within the last 6 months: Unstable angina pectoris,
Congestive heart failure (NYHA = Grade 2), Acute myocardial infarction, Stroke or transient
ischemic attack.

Known hypersensitivity to the active or inactive excipients of AZD6094. Uncontrolled
hypertension (BP =150/95 mmHg despite medical therapy) Mean resting correct QT interval
(QTcF) >470 msec for women and >450 msec for men or factors that may increase the risk of
QTcF prolongation such as chronic hypokalaemia not correctable with supplements, congenital
or familial long QT syndrome, or family history of unexplained sudden death under 40 years
of age in first degree relatives or any concomitant medication known to prolong the QT
interval and cause Torsade de Pointes.

Any clinically important abnormalities in rhythm, conduction or morphology of resting
electrocardiograms (ECGs), e.g. complete left bundle branch block, third degree heart
block, second degree heart block, PR interval >250 msec. Serious underlying medical
condition at the time of treatment that would impair the ability of the patient to receive
protocol treatment.

Active hepatitis B (positive HBsAg result) or hepatitis C (HCV). Patients with a past or
resolved HBV infection are eligible if negative for HBsAg and positive for anti-HBc or
positive for HBsAg, but for > 6 months have had normal transaminases and HBV DNA levels
between 0-2000 IU/ml (inactive carrier state) and willing to start and maintain antiviral
treatment for at least the duration of the study. HBV DNA levels > 2000 IU/ml but on
prophylactic antiviral treatment for the past 3 months and will maintain the antiviral
treatment during the study. Patients with positive HCV antibody are eligible only if the
polymerase chain reaction is negative for HCV RNA.

Known serious active infection including, but not limited to, tuberculosis, or human
immunodeficiency virus (positive HIV 1/2 antibodies).

Presence of other active cancers, or history of treatment for invasive cancer, within the
last 5 years. Patients with Stage I cancer who have received definitive local treatment at
least 3 years previously, and are considered unlikely to recur are eligible. All patients
with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are
patients with history of non-melanoma skin cancer.

Women who are either pregnant or breast feeding. Previous allogeneic bone marrow transplant
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.



Age minimum: 18 Years
Age maximum: 130 Years
Gender: All

Health Condition(s) or Problem(s) studied

Advanced Non Small Cell Lung Cancer

Intervention(s)

Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)

Drug: Part D - AZD9291 in combination with AZD6094

Drug: Part A - AZD9291 in combination with AZD6094

Drug: Part A - AZD9291 in combination with intermittent selumetinib

Drug: Part C - AZD6094 monotherapy (Japan only)

Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)

Drug: Part A - AZD9291 in combination with MEDI4736

Drug: Part B - AZD9291 in combination with selumetinib

Drug: Part B - AZD9291 in combination with AZD6094

Drug: Part C - AZD9291 in combination with AZD6094 (Japan only)

Drug: Part B - AZD9291 in combination with MEDI4736

Primary Outcome(s)

Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib [Time Frame: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.]

Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib [Time Frame: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.]

Secondary Outcome(s)

AUCss after multiple dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours]

Duration of response [Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study.]

Time dependency of PK after multiple dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1]

Progression free survival [Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study.]

Disease control rate [Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study.]

Objective response rate [Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study.]

Terminal half life after single dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours]

Tmax after single dosing [Time Frame: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours]

Volume of distribution after single dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours]

AUC0-t after single dosing [Time Frame: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours]

CLss/f after multiple dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours]

Cssmin after multiple dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times for the duration of treatment.]

Overall survival [Time Frame: Confirmed during the FUP period and at least every 12 weeks until the data cut-off for the primary analysis and determination that no further OS collection is needed, approximately 5 years, death, or full withdrawal of consent, whichever comes first.]

AUC after single dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours]

AUC0-24 after single dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours]

Cmax after single dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours]

Cssmax after multiple dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours]

CL/f after single dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours]

Percentage change in tumour size [Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study.]

Rac after multiple dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1]

Tssmax after multiple dosing [Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours]

Secondary ID(s)

2016-004752-29

D5160C00006

Source(s) of Monetary Support

Please refer to primary and secondary sponsors