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Savolitinib Plus Osimertinib Versus Platinum-based Doublet Chemotherapy in Participants With Non-Small Cell Lung Cancer Who Have Progressed on Osimertinib Treatment (SAFFRON)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05261399
Recruitment Status : Recruiting
First Posted : March 2, 2022
Last Update Posted : December 12, 2023
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
Clinical study to investigate the efficacy and safety of savolitinib in combination with osimertinib versus platinum-based doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on treatment with Osimertinib.

Condition or disease Intervention/treatment Phase
Carcinoma Non-Small-Cell Lung Drug: Savolitinib Drug: Osimertinib Drug: Pemetrexed Drug: Cisplatin Drug: Carboplatin Phase 3

Detailed Description:

This is a multicentre, Phase III, randomised, open-label study to investigate the efficacy and safety of savolitinib administered orally in combination with osimertinib versus platinum-based doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on first- or second-line treatment with osimertinib as the most recent therapy.

Approximately 324 participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC will be randomly assigned to study intervention with 1:1 ratio.

Patients will be treated until either objective progression of disease (PD) by Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1) is assessed by the investigator, unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is met.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 324 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Treatment
Official Title: A Phase III, Randomised, Open-Label Study of Savolitinib in Combination With Osimertinib Versus Platinum-Based Doublet Chemotherapy in Participants With EGFR Mutated, MET-Overexpressed and/or Amplified, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed on Treatment With Osimertinib (SAFFRON).
Actual Study Start Date : August 3, 2022
Estimated Primary Completion Date : May 30, 2025
Estimated Study Completion Date : November 30, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

Arm Intervention/treatment
Active Comparator: Chemotherapy
Pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC5) on Day 1 of 21-day cycles (Q3W) for 4 cycles, followed by pemetrexed maintenance (500 mg/m2) Q3W
Drug: Pemetrexed
Pemetrexed (500 mg/m2) Administrative route : IV infusion
Other Name: NAP

Drug: Cisplatin
Cisplatin (75 mg/m2) or Administrative route : IV infusion
Other Name: NAP

Drug: Carboplatin
Carboplatin (AUC5) Administrative route : IV infusion
Other Name: NAP

Experimental: Savolitinib + Osimertinib
300 mg savolitinib BID plus 80 mg osimertinib QD
Drug: Savolitinib
300 mg savolitinib (3 × 100 mg tablets twice daily) Administrative route : oral
Other Name: AZD6094, HMPL-504, volitinib

Drug: Osimertinib

80 mg osimertinib

(1 × 80 mg tablet once daily) Administrative route : oral

Other Name: AZD9291, Tagrisso




Primary Outcome Measures :
  1. Progression-free survival (PFS) / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on osimertinib. [ Time Frame: Approximately 55 months post first subject randomized ]
    Defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. PFS is assessed by Investigator.


Secondary Outcome Measures :
  1. Overall Survival (OS) /savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. [ Time Frame: Approximately 55 months post first subject randomized. ]
    Defined as time from randomisation until the date of death due to any cause.

  2. Progression-free survival (PFS) / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed, locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. [ Time Frame: Approximately 55 months post first subject randomized ]
    Defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. PFS is assessed by Investigator.

  3. Overall Survival (OS) / savolitinib in combination with osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed by IHC, locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. [ Time Frame: Approximately 55 months post first subject randomized ]
    Defined as time from randomisation until the date of death due to any cause.

  4. Objective response rate (ORR) savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. [ Time Frame: Approximately 55 months post first subject randomized ]
    ORR defined as the proportion of participants who have BOR of a CR or PR, as determined by BICR per RECIST 1.1.

  5. Participant-reported pulmonary core symptoms / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on osimertinib. [ Time Frame: Approximately 55 months post first subject randomized ]

    TTD in pulmonary core symptoms (dyspnoea, cough, and chest pain) as measured by the NSCLC-SAQ.

    TTD is defined as the time from randomisation until the date of deterioration.


  6. Pharmacokinetics (PK) of savolitinib. [ Time Frame: 6 weeks after last patient dosed ]
    Plasma concentrations of savolitinib and its metabolites.

  7. Disease control rate (DCR) / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. [ Time Frame: Approximately 55 months post first subject randomized ]
    DCR defined as the proportion of participants who have BOR of a CR, PR, or stable disease, as determined by BICR per RECIST 1.1.

  8. Time to discontinuation of treatment (TDT) or death / savolitinib + osimertinib vs platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on osimertinib [ Time Frame: Approximately 55 months post first subject randomized ]
    TDT or death is defined as the time from date of randomisation to the earlier of the date of study intervention discontinuation or death.

  9. Tumor shrinkage / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. [ Time Frame: Approximately 55 months post first subject randomized ]
    Tumour shrinkage defined as percentage change in tumour size in accordance with RECIST 1.1.

  10. Duration of response (DoR) / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. [ Time Frame: Approximately 55 months post first subject randomized ]
    DoR defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by BICR, or death in the absence of disease progression.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provision of signed and dated written ICF prior to any mandatory and non-mandatory study-specific procedures, sampling and analyses.
  • Participant must be ≥18 years (≥ 20 years of age in Japan) at the time of signing the informed consent. All genders are permitted.
  • Histologically or cytologically confirmed locally advanced or metastatic NSCLC which is not amenable to curative therapy.
  • Must have at least one documented sensitising EGFR mutation: exon19 deletion, L858R mutation, and/or T790M.
  • Documented radiologic progression on first- or second-line treatment with osimertinib as the most recent anti-cancer therapy.
  • Mandatory provision of FFPE tumour tissue.
  • MET overexpression and/or amplification in tumour specimen collected following progression on prior osimertinib treatment.
  • Measurable disease as defined by RECIST 1.1.
  • Adequate haematological, liver, renal and cardiac functions, and coagulation parameters.
  • ECOG performance status of 0 or 1.

Exclusion Criteria:

  • Predominant squamous NSCLC, and small cell lung cancer.
  • Prior or current treatment with a third-generation EGFR-TKI other than Osimertinib.
  • Prior or current treatment with savolitinib or another MET inhibitors.
  • Spinal cord compression or brain metastases, unless asymptomatic and are stable.
  • History or active leptomeningeal carcinomatosis.
  • Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 with the exception of alopecia, haemoglobin ≥ 9.0 g/dL, and Grade 2 prior platinum-therapy related neuropathy.
  • Active/unstable cardiac diseases currently or within the last 6 months, clinically significant ECG abnormalities, and/or factors/medications that may affect QTc intervals.
  • History of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement.
  • Known serious active infection including, but not limited to, tuberculosis, or HIV, HBV or HCV or gastrointestinal disease.
  • Receipt of live attenuated vaccine (including against COVID-19) within 30 days prior to the first dose of study intervention.
  • Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD.
  • Participants currently receiving medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP)3A4 or strong inhibitors of CYP1A2.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05261399


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
Show Show 271 study locations
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Shun Lu, Prof,MD,PhD, Shanghai Chest Hospital, Shanghai JiaoTong University, #241 Huai Hai Road (west), Shanghai, China.
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT05261399    
Other Study ID Numbers: D5087C00001
2021-006374-24 ( EudraCT Number )
First Posted: March 2, 2022    Key Record Dates
Last Update Posted: December 12, 2023
Last Verified: December 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
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 deidentified 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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Savolitinib
Osimertinib
EGFR
Amplified
Metastatic
MET Driven
carcinoma
NSCLC
overexpressed
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carboplatin
Pemetrexed
Osimertinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors