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Trial registered on ANZCTR


Registration number
ACTRN12622000973718
Ethics application status
Approved
Date submitted
29/05/2022
Date registered
11/07/2022
Date last updated
6/11/2023
Date data sharing statement initially provided
11/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
SHERLOCK: Phase 2 trial of sotorasib in combination with carboplatin-pemetrexed and bevacizumab-biosimilar as first line treatment for advanced non-squamous non-small cell lung cancer
with KRAS G12C mutation
Scientific title
SHERLOCK: Phase 2 trial of sotorasib in combination with carboplatin-pemetrexed and bevacizumab-biosimilar as first line treatment for advanced non-squamous non-small cell lung cancer
with KRAS G12C mutation
Secondary ID [1] 307187 0
TOGA 21/011
Secondary ID [2] 307188 0
CTC 0377
Universal Trial Number (UTN)
Trial acronym
SHERLOCK
Linked study record

Health condition
Health condition(s) or problem(s) studied:
advanced non-squamous non-small cell lung cancer
with KRAS G12C mutation
 326412 0
Condition category
Condition code
Cancer 323697 323697 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Induction: 4 x 3 weekly cycles of
Sotorasib 960mg oral tablets daily plus
Pemetrexed 500mg/m2 Day 1 every 3 weeks via intravenous infusion plus
Carboplatin total dose not exceeding 750mg (variable depending on age, weight, gender) and calculated for each participant using the Calvert method on Day 1 every 3 weeks via intravenous infusion plus
Bevacisumab-biosimilar 15 mg/kg Day 1 every 3 weeks via intravenous infusion

Maintenance:
Sotorasib 960mg oral tablets daily continuous
Pemetrexed 500mg/m2 Day 1 every 3 weeks via intravenous infusion plus
Bevacisumab-biosimilar 15 mg/kg Day 1 every 3 weeks via intravenous infusion

Until disease progression, or unmanageable toxicity, or withdrawal of consent
Adherence to the regime will be monitored via medication charts and review of drug tablet returns at scheduled visits.
Intervention code [1] 323673 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331447 0
To evaluate the objective tumour response rate (OTRR = confirmed response + Partial Response) assessed according to RECIST 1.1
Timepoint [1] 331447 0
CT scans performed at baseline, then every 8 weeks until disease progression
Secondary outcome [1] 409918 0
To evaluate progression free survival - defined as the interval from date of randomisation to the date of first evidence of disease progression or death, whichever occurs first.
Timepoint [1] 409918 0
CT scans performed at baseline, then every 8 weeks until disease progression
Secondary outcome [2] 409919 0
To evaluate duration of response. Duration of response (DoR) is defined as the interval from date of first tumour assessment with an outcome of response (date when either CR or PR is first determined) to the date of first evidence of disease progression or death, whichever occurs first. Disease progression is defined according to
RECIST version 1.1
Timepoint [2] 409919 0
CT scans performed at baseline, then every 8 weeks until disease progression
Secondary outcome [3] 409920 0
To evaluate depth of response. Depth of response is defined as the percentage of tumour shrinkage, based on the sum of the longest diameters of all target lesions observed at the lowest point (nadir), compared with the sum of their ongest diameters at baseline.
Timepoint [3] 409920 0
CT scans performed at baseline, then every 8 weeks until disease progression
Secondary outcome [4] 409921 0
To evaluate overall survival
Timepoint [4] 409921 0
Defined as the time from randomisation to the date of death due to any cause. After discontinuation of study treatment, participants who are unable to attend the clinic may be followed by telephone calls to their home or other medical staff.
Secondary outcome [5] 409922 0
To evaluate adverse events assessed according to CTCAE v5.0, PRO-CTCAE v1.0, and Patient Disease And Treatment Assessment (D.A.T.A) Form v1.0
Timepoint [5] 409922 0
Adverse events will be assessed every 3 weeks from the first dose of study treatment until 30 days after last dose.

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older, with either:
a) newly diagnosed, treatment naïve metastatic (Stage IV) non-squamous NSCLC, or
b) recurrent non-squamous NSCLC with no disease progression for at least 6 months following prior curative lung surgery and (neo)adjuvant chemotherapy, or prior curative concurrent chemoradiotherapy and immunotherapy maintenance, for non-resectable stage III cancer.
2. Presence of KRAS G12C mutation in tumour tissue
3. Sufficient tumour tissue should be available for molecular profiling by Next Generation Sequencing (NGS) or results available from molecular profiling of tumour tissue by NGS. If there is insufficient tissue for NGS testing, a repeat biopsy is strongly recommended. Acceptable platforms include, but are not limited to: FoundationOne Tissue CDx, Illumina TruSight Oncology 500 (TSO500)
4. Measurable disease according to RECIST 1.1. Lesions previously irradiated are not considered measurable unless they have unequivocally progressed after radiation.
5. ECOG performance status of 0 or 1
6. Adequate bone marrow function within 14 days prior to registration:
• Platelets greater than or equal to 100 x 109/L
• Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L
• Haemoglobin greater than or equal to 90 g/L
• International normalized ratio (INR) less than or equal to 1.5
• activated partial thromboplastin time (aPTT) less than or equal to 1.5 x ULN
7. Adequate liver function within 14 days prior to registration:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x institutional upper limit of normal (ULN) (or less than or equal to 5 x ULN if liver metastases are present).
8. Adequate renal function with no proteinuria within 14 days prior to registration:
• Creatinine clearance greater than or equal to 60 mL/min. This can be determined using any of the following: 51Cr-EDTA, 99mTc-DTPA renography, 24-hour urine collection for creatinine clearance, or estimated using the Cockcroft-Gault formula
• Urine dipstick with no proteinuria (i.e. either 0, trace, or 1+). If urine dipstick is greater than 1 then 24-hour urine collection is required, and must demonstrate less than or equal to 500 mg protein per day
9. QTc less than or equal to 470 msec in females and less than or equal to 450 msec in males (based on average of screening triplicates)
10. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
11. Signed, written informed consent (main study and tissue banking).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous treatment with sotorasib, or KRAS G12C specific inhibitor, or pan-KRAS inhibitor
2. Concurrent driver mutation (including EGFR, ALK, ROS1, BRAF) where an approved targeted therapy is available
3. Mixed histology with any small cell or squamous component
4. Evidence of active bleeding or bleeding risk, including:
• a tumour that compresses or invades major blood vessels or tumour cavitation that in the opinion of the investigator is likely to bleed
• History of haemoptysis (>2.5 mL per event) in the last 3 months or severe bleeding
• Bleeding disorders, haemorrhagic diathesis
• Chronic systemic anticoagulation with aspirin > 100 mg/day, clopidogrel > 75 mg/day, ticagrelor > 90 mg BD, more than one anti-platelet drug, warfarin, heparin, enoxaparin, and other direct oral anticoagulants (e.g. apixaban, rivaroxaban, etc)
5. Medically uncontrolled hypertension or systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg. If “white coat” hypertension is suspected, a 24-hour continuous blood pressure recording is required to accurately determine blood pressure.
6. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months prior to registration, unstable arrhythmias, or unstable angina
7. Significant peripheral vascular disease or cerebrovascular disease (including stroke or transient ischaemic attack within 6 months prior to registration)
8. Concurrent medical illness that may jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety
9. Severe infection within 4 weeks prior to registration including, but not limited to hospitalisation for management of infection, bacteraemia or sepsis.
10. Active hepatitis B, hepatitis C, or HIV. Chronic hepatitis B carrier with undetectable hepatitis DNA level is allowed. Serological testing is not mandatory unless clinically indicated.
11. Major surgery within 28 days prior to registration
12. Significant gastrointestinal disorder that results in significant malabsorption, requirement for intravenous alimentation, or inability to swallow oral tablet medication
13. History of a malignancy within 5 years prior to registration except for non-melanomatous carcinoma of the skin
14. Spinal cord compression, symptomatic and unstable brain metastases, except for those participants who have completed definitive therapy, are not on steroids equivalent to oral prednisone of > 10 mg/day, and have a stable neurological status for at least 2 weeks after commencement of the definitive therapy. Participants with untreated asymptomatic brain metastases can be eligible for inclusion if immediate definitive treatment is not indicated
15. Leptomeningeal disease
16. Known allergy or hypersensitivity to any of the study drugs or their excipients
17. Life expectancy of less than 3 months
18. Current enrolment or participation in another clinical study with an unregistered investigational product during the last 12 months, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study, in which case eligibility should be discussed with the Study Chair by contacting the NHMRC CTC.
19. Serious medical or psychiatric conditions that might limit the ability of the participant to comply with the protocol.
20. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Using Simon 2-stage design, 49 evaluable patients will provide
80% power to exclude a clinically uninteresting OTRR of 29% or
less in favour of a clinically interesting rate of 46% or greater,
with a one-sided alpha of 5%. If there are 8 or fewer responses
in the first 28 patients, consideration will be given to stopping the
study for futility. The null hypothesis will be rejected if 20 or more
objective tumour responses are observed in 49 evaluable
patients. A total of 52 patients will be recruited to account allow
for patient dropout.
The uninteresting OTRR of 29% or less is based on the lower
bound of the 95% CI reported for sotorasib monotherapy. OTRR
of 46% or greater is of clinical interest, as it exceeds the
performance of either sotorasib monotherapy or the combination
of carboplatin/pemetrexed/bevacizumab.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/08/2022
Actual
23/09/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
52
Accrual to date
26
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,VIC
Recruitment hospital [1] 24175 0
GenesisCare – North Shore - St Leonards
Recruitment hospital [2] 24176 0
The Northern Beaches Hospital - Frenchs Forest
Recruitment hospital [3] 24177 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 24178 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [5] 24179 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [6] 24180 0
The Prince Charles Hospital - Chermside
Recruitment hospital [7] 24181 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [8] 24182 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [9] 24183 0
Liverpool Hospital - Liverpool
Recruitment hospital [10] 24677 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [11] 24944 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [12] 25146 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 39707 0
2065 - St Leonards
Recruitment postcode(s) [2] 39708 0
2086 - Frenchs Forest
Recruitment postcode(s) [3] 39709 0
2747 - Kingswood
Recruitment postcode(s) [4] 39710 0
3000 - Melbourne
Recruitment postcode(s) [5] 39711 0
3084 - Heidelberg
Recruitment postcode(s) [6] 39712 0
4032 - Chermside
Recruitment postcode(s) [7] 39713 0
4575 - Birtinya
Recruitment postcode(s) [8] 39714 0
3168 - Clayton
Recruitment postcode(s) [9] 39715 0
2170 - Liverpool
Recruitment postcode(s) [10] 40297 0
2444 - Port Macquarie
Recruitment postcode(s) [11] 40595 0
5011 - Woodville South
Recruitment postcode(s) [12] 40814 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 311494 0
Commercial sector/Industry
Name [1] 311494 0
Amgen Australia Pty Limited
Country [1] 311494 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
c/o Research Portfolio, F23 Administration Building, Level 3, Corner of Eastern Avenue and City Road, University of Sydney, NSW 2006
Country
Australia
Secondary sponsor category [1] 312894 0
Other Collaborative groups
Name [1] 312894 0
Thoracic Oncology Group of Australasia (TOGA)
Address [1] 312894 0
Level 6, 1 Chifley Square, Sydney, NSW 2000
Country [1] 312894 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310954 0
SLHD HREC
Ethics committee address [1] 310954 0
Clinical Trials Executive Officer
Research Ethics & Governance Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 310954 0
Australia
Date submitted for ethics approval [1] 310954 0
24/01/2022
Approval date [1] 310954 0
14/03/2022
Ethics approval number [1] 310954 0

Summary
Brief summary
The purpose of the study is to test the effectiveness of a new treatment combination for patients with non-small cell lung cancer (NSCLC) whose tumour has a specific type of gene mutation called KRAS G12C. This mutation is believed to cause the tumour to grow and spread.

Who is it for?
You may be eligible for this study if you are aged 18 years and older, with either:
a) newly diagnosed, treatment naïve metastatic (Stage IV) non-squamous NSCLC, or
b) recurrent non-squamous NSCLC with no disease progression for at least 6 months following prior curative lung surgery and (neo)adjuvant chemotherapy, or prior curative concurrent chemoradiotherapy and immunotherapy maintenance, for non-resectable stage III cancer.

Study details
The new drug, sotorasib, is a tablet treatment which is targeted against the KRAS G12C gene mutation. Early results show that sotorasib is moderately active when given alone. The effectiveness of sotorasib might be increased when given in combination with other anti-cancer drugs. This study will investigate whether sotorasib used in combination with two chemotherapy drugs (called carboplatin and pemetrexed) and bevacizumab (which improves anti-cancer drug delivery), can result in better outcomes. The combination of carboplatin-pemetrexed-bevacizumab is a proven treatment for NSCLC.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119482 0
A/Prof Chee Khoon Lee
Address 119482 0
St George Hospital
Gray Street
Kogarah NSW 2217
AUSTRALIA
Country 119482 0
Australia
Phone 119482 0
+61 2 9562 5365
Fax 119482 0
Email 119482 0
[email protected]
Contact person for public queries
Name 119483 0
Ashley Douglas
Address 119483 0
NHMRC Clinical Trials Centre
Locked bag 77,
Camperdown NSW 1450,
Australia
Country 119483 0
Australia
Phone 119483 0
+61 2 9562 5000
Fax 119483 0
Email 119483 0
[email protected]
Contact person for scientific queries
Name 119484 0
Ashley Douglas
Address 119484 0
NHMRC Clinical Trials Centre
Locked bag 77,
Camperdown NSW 1450,
Australia
Country 119484 0
Australia
Phone 119484 0
+61 2 9562 5000
Fax 119484 0
Email 119484 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Participant trial data will be entered directly into a web based CRF held by the NHMRC Clinical Trials Centre, University of Sydney. Access will only be granted to the research staff directly involved with the trial. Individual participant data will not be made publicly available. Only grouped data which does not identify individual participants will be published.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIP2.11-03 Synergistic Co-Targeting Of MYC And KRAS In Lung Cancer By Novel Ligand-Directed Inverted Chimeric RNAi Molecules2023https://doi.org/10.1016/j.jtho.2023.09.633
N.B. These documents automatically identified may not have been verified by the study sponsor.