Clinical trial NCT02143466: AZD9291 in Combination With Ascending Doses of Novel Therapeutics
Official 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).
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Advanced Non Small Cell Lung Cancer
Keywords: Phase I
Safety
Tolerability
Efficacy
Anti-tumour
AZD9291
AZD6094
MEDI4736
Osimertinib
Savolitinib
Selumetinib
Durvalumab
Ascending Doses
Expansion cohorts
EGFR
Advanced Non-Small Cell Lung Cancer
Tyrosine Kinase Inhibitors
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-05-21
Enrollment: 344
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer

Detailed description: This is a Phase Ib, open-label, multicentre study of AZD9291 administered orally in combination with novel therapeutics (AZD6094 or selumetinib (AZD6244, ARRY142886)) to patients with EGFRm+ advanced NSCLC. The study has been designed to allow an investigation of the optimal combination dose and schedule whilst ensuring the safety of patients with intensive safety monitoring. There are three main parts to this study; Part A, Combination dose finding and Parts B and D, Dose expansion. Part C, AZD6094 dose finding sub-study in advanced solid tumour patients is ongoing in Japan.

AZD9291 (osimertinib) is a potent irreversible inhibitor of both the single epidermal growth factor receptor sensitising mutation positive (EGFRm+) (tyrosine kinase inhibitor \[TKI\] sensitivity-conferring mutation) and dual EGFRm+/T790M+ (TKI resistance-conferring mutation) receptor forms of EGFR. AZD9291 therefore has the potential to provide clinical benefit to patients with advanced non-small cell lung cancer (NSCLC) harbouring both the single sensitivity mutations and the resistance mutation following prior therapy with an EGFR TKI. AZD9291 (osimertinib) was awarded FDA accelerated approval in November 2015, followed by conditional approval in the EU, full approval in Japan and additional markets in 2016, for the treatment of patients with EGFR T790M+ NSCLC who have progressed on or after EGFR TKI therapy.

Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.

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Eligibility 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.

Primary outcomes:
measure: 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
timeFrame: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.
measure: Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib
timeFrame: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.
Secondary outcomes:
measure: Cmax after single dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours
measure: Tmax after single dosing
timeFrame: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours
measure: AUC after single dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours
measure: AUC0-t after single dosing
timeFrame: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours
measure: AUC0-24 after single dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours
measure: Terminal half life after single dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours
measure: CL/f after single dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours
measure: Volume of distribution after single dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours
measure: Cssmax after multiple dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours
measure: Tssmax after multiple dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours
measure: Cssmin after multiple dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times for the duration of treatment.
measure: AUCss after multiple dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours
measure: CLss/f after multiple dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours
measure: Rac after multiple dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1
measure: Time dependency of PK after multiple dosing
timeFrame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1
measure: Objective response rate
timeFrame: At baseline and every 6 weeks until disease progression or withdrawal from study.
measure: Disease control rate
timeFrame: At baseline and every 6 weeks until disease progression or withdrawal from study.
measure: Duration of response
timeFrame: At baseline and every 6 weeks until disease progression or withdrawal from study.
measure: Percentage change in tumour size
timeFrame: At baseline and every 6 weeks until disease progression or withdrawal from study.
measure: Progression free survival
timeFrame: At baseline and every 6 weeks until disease progression or withdrawal from study.
measure: Overall survival
timeFrame: 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.
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New York
country: United States
facility: Research Site
state: New York
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Chuo-ku
country: Japan
facility: Research Site
city: Habikino-shi
country: Japan
facility: Research Site
city: Hirakata-shi
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Cheongju-si
country: Korea, Republic of
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Olsztyn
country: Poland
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Chelyabinsk
country: Russian Federation
facility: Research Site
city: Krasnoyarsk
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Omsk
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: Kaohsiung City
country: Taiwan
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
Study officials:
affiliation: Dana-Faber Cancer Institute
name: Pasi A Jänne, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ahn MJ, Cho BC, Ou X, Walding A, Dymond AW, Ren S, Cantarini M, Janne PA. Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial. J Thorac Oncol. 2022 May;17(5):718-723. doi: 10.1016/j.jtho.2022.01.012. Epub 2022 Feb 15.
citation: Yoh K, Hirashima T, Saka H, Kurata T, Ohe Y, Hida T, Mellemgaard A, Verheijen RB, Ou X, Ahmed GF, Hayama M, Sugibayashi K, Oxnard GR. Savolitinib +/- Osimertinib in Japanese Patients with Advanced Solid Malignancies or EGFRm NSCLC: Ph1b TATTON Part C. Target Oncol. 2021 May;16(3):339-355. doi: 10.1007/s11523-021-00806-5. Epub 2021 May 3.
citation: Oxnard GR, Yang JC, Yu H, Kim SW, Saka H, Horn L, Goto K, Ohe Y, Mann H, Thress KS, Frigault MM, Vishwanathan K, Ghiorghiu D, Ramalingam SS, Ahn MJ. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann Oncol. 2020 Apr;31(4):507-516. doi: 10.1016/j.annonc.2020.01.013. Epub 2020 Jan 24.
citation: Sequist LV, Han JY, Ahn MJ, Cho BC, Yu H, Kim SW, Yang JC, Lee JS, Su WC, Kowalski D, Orlov S, Cantarini M, Verheijen RB, Mellemgaard A, Ottesen L, Frewer P, Ou X, Oxnard G. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 2020 Mar;21(3):373-386. doi: 10.1016/S1470-2045(19)30785-5. Epub 2020 Feb 3.