AZD9291 in Combination With Ascending Doses of Novel Therapeutics
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).
2 other identifiers
interventional
344
8 countries
42
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
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Aug 2014
Longer than P75 for phase_1
42 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 9, 2014
CompletedFirst Posted
Study publicly available on registry
May 21, 2014
CompletedStudy Start
First participant enrolled
August 5, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 4, 2020
CompletedStudy Completion
Last participant's last visit for all outcomes
December 31, 2026
ExpectedApril 24, 2026
April 1, 2026
5.6 years
May 9, 2014
April 23, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
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
Part A: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.
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
Part B: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib in patients with locally advanced or metastatic NSCLC, who have progressed on prior therapy with an EGFR TKI agent. Part C monotherapy cohort (Japan only): To investigate and confirm the safety and tolerability of AZD6094 when given orally to Japanese patients with advanced solid malignancies. Part C combination cohort (Japan only): To investigate the safety and tolerability of AZD9291 when given orally to Japanese patients with EGFRm+ NSCLC in combination with AZD6094 who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation. Part D: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 (300 mg OD) in patients with locally advanced or metastatic EGFRm+ NSCLC.
Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.
Secondary Outcomes (21)
Cmax after single dosing
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
Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours
AUC after single dosing
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
Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours
AUC0-24 after single dosing
Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours
- +16 more secondary outcomes
Study Arms (4)
AZD6094
EXPERIMENTALAZD9291 in combination with AZD6094
Selumetinib
EXPERIMENTALAZD9291 in combination with selumetinib
MEDI4736
EXPERIMENTALAZD9291 in combination with MEDI4736. 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.
AZD6094 (monotherapy)
EXPERIMENTALAZD6094 in monotherapy (for Japan only)
Interventions
Part A - AZD9291 and AZD6094 administered in different doses to investigate the safety and tolerability of this combination and define the combination dose for further clinical evaluation in Part B.
Part A - AZD9291 and selumetinib (continuous treatment) administered in different doses to investigate the safety and tolerability of this combination in Asian subjects and to define the combination dose for further clinical evaluation in Part B.
Part A - AZD9291 and selumetinib (continuous treatment) administered in different doses to investigate the safety and tolerability of this combination in non-Asian subjects and to define the combination dose for further clinical evaluation in Part B.
Part A - AZD9291 and selumetinib (intermittent treatment) administered in different doses to investigate the safety and tolerability of this combination and to define the combination dose for further clinical evaluation in Part B.
Part A - AZD9291 and MEDI4736 administered in different doses to investigate the safety and tolerability of this combination and to define the combination dose for further clinical evaluation in Part B. Note: 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.
Part B - AZD9291 and AZD6094 administered in the dose identified in Part A (AZD9291 80mg OD + AZD6094 600mg OD) to further investigate the safety and tolerability of this combination.
Part B - AZD9291 and selumetinib administered in the dose identified in Part A (AZD9291 80mg OD + selumetinib 75 mg BD intermittent \[4 days on/3 days off\]) to further investigate the safety and tolerability of this combination.
Part B - AZD9291 and MEDI4736 administered in the dose identified in Part A to further investigate the safety and tolerability of this combination. Note: 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.
Part C - AZD6094 monotherapy to assess the safety, tolerability and pharmacokinetics of the monotherapy of AZD6094 in Japanese patients with advanced NSCLC.
Part C combination cohort - AZD9291 80mg OD administered in combination with AZD6094 400mg OD (AZD6094 dose in which DLTs have not been identified in the Japanese monotherapy cohort) in order to confirm the safety, tolerability, pharmacokinetics and preliminary anti-tumor activities of this combination in Japanese subjects. The 400mg OD dosing schedule will be initiated in the first cohort. The dose may be subsequently reduced in further cohorts in response to emerging safety, or PK findings or other reasons identified in the savolitinib programme.
Part D - AZD9291 80mg OD administered in combination with AZD6094 300mg OD to further evaluate the safety, tolerability, pharmacokinetics and antitumor activity in terms of ORR and PFS in patients with locally advanced or metastatic cMET positive EGFRm+ and T790M-negative NSCLC, following progression on EGFR-TKI treatment. The choice of AZD6094 dose of 300 mg is based on results from preclinical and clinical studies. Clinical testing of the 300 mg OD dose will enable better assessment of impact of lower AZD6094 exposure on overall tolerability and hepatotoxicity risk as well as exploration of the efficacy and overall safety profiles with a dose meaningfully lower than the current dose of 600 mg OD.
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- AstraZenecalead
Study Sites (42)
Research Site
Atlanta, Georgia, 30329, United States
Research Site
Boston, Massachusetts, 02114, United States
Research Site
Boston, Massachusetts, 02215, United States
Research Site
New York, New York, 10065, United States
Research Site
Philadelphia, Pennsylvania, 19111, United States
Research Site
Nashville, Tennessee, 37232, United States
Research Site
Calgary, Alberta, T2N 4N2, Canada
Research Site
Edmonton, Alberta, T6G 1Z2, Canada
Research Site
Chūōku, 104-0045, Japan
Research Site
Habikino-shi, 583-8588, Japan
Research Site
Hirakata-shi, 573-1191, Japan
Research Site
Kashiwa, 227-8577, Japan
Research Site
Nagoya, 460-0001, Japan
Research Site
Nagoya, 464-8681, Japan
Research Site
Gdansk, 80-952, Poland
Research Site
Krakow, 31-202, Poland
Research Site
Olsztyn, 10-357, Poland
Research Site
Poznan, 60-569, Poland
Research Site
Warsaw, 02-781, Poland
Research Site
Chelyabinsk, 454087, Russia
Research Site
Krasnoyarsk, 660133, Russia
Research Site
Moscow, 115478, Russia
Research Site
Omsk, 644013, Russia
Research Site
Saint Petersburg, 195271, Russia
Research Site
Saint Petersburg, 197002, Russia
Research Site
Saint Petersburg, 197022, Russia
Research Site
Saint Petersburg, 197342, Russia
Research Site
Saint Petersburg, 197758, Russia
Research Site
Cheongju-si, 28644, South Korea
Research Site
Goyang-si, 10408, South Korea
Research Site
Seongnam-si, 13620, South Korea
Research Site
Seoul, 03722, South Korea
Research Site
Seoul, 05505, South Korea
Research Site
Seoul, 6351, South Korea
Research Site
Kaohsiung City, 82445, Taiwan
Research Site
Kaohsiung City, 83301, Taiwan
Research Site
Tainan, 704, Taiwan
Research Site
Taipei, 10002, Taiwan
Research Site
Taipei, 112, Taiwan
Research Site
Taipei, 235, Taiwan
Research Site
Kyiv, 03022, Ukraine
Research Site
Vinnytsia, 21029, Ukraine
Related Publications (4)
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.
PMID: 35181499DERIVEDYoh 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.
PMID: 33939068DERIVEDOxnard 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.
PMID: 32139298DERIVEDSequist 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.
PMID: 32027846DERIVED
MeSH Terms
Interventions
Study Officials
- PRINCIPAL INVESTIGATOR
Pasi A Jänne, MD, PhD
Dana-Faber Cancer Institute
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
May 9, 2014
First Posted
May 21, 2014
Study Start
August 5, 2014
Primary Completion
March 4, 2020
Study Completion (Estimated)
December 31, 2026
Last Updated
April 24, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will share
- Time Frame
- AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
- Access Criteria
- When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.