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Trial registered on ANZCTR


Registration number
ACTRN12621000312842
Ethics application status
Approved
Date submitted
18/01/2021
Date registered
22/03/2021
Date last updated
22/10/2021
Date data sharing statement initially provided
22/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program and ASPiRATION subprogram, Addendum 14 – substudy 32: Alectinib
Scientific title
A Single arm, open label, phase II trial of tumour response to alectinib in patients with advanced tumours harbouring ALK gene alterations detected by comprehensive genomic profiling
Secondary ID [1] 303158 0
CTC 0141 – addendum 14
Universal Trial Number (UTN)
U1111-1263-7887
Trial acronym
MoST Addendum 14
Linked study record
This record is an addendum to the MoST framework (ACTRN12616000908437). The MoST framework protocol consists of 1/molecular screening (genomic analysis to determine whether participants are suitable for a sub-study) and 2/ sub-study design structure (study treatment for specific genomic expression/participant population). Additionally, the sub-study shares the same study objectives and outcomes as the framework. Hence, this is a substudy that linked to ACTRN12616000908437.

Health condition
Health condition(s) or problem(s) studied:
Cancer 320279 0
ALK gene alterations 320280 0
Non-small cell lung cancer 320281 0
Condition category
Condition code
Cancer 318208 318208 0 0
Any cancer
Cancer 318209 318209 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will recieve continuous alectinib 600mg capsules, twice a day until disease progression, participant withdrawal or unnaceptable toxicity.

If participants experience any severe (grade 3-4) adverse events, treatment will be withheld until the adverse event is resolved (grade 0-1). Once the adverse event is resolved, the patient should continue on their prescribed dose of alectinib.

If participants experience intolerance toxicity, alectinib dose may be reduced to 540mg twice daily, and then to 300mg twice daily if participants experience further intolerance toxicity. If a third dose reduction is required, the patient should discontinue study treatment.

There is no maximum number of treatment cycles that alectinib will be taken for. Participants will continuously receive alectinib until disease progression is documented or when the participants experience intolerable toxicity or withdraws for another reason. Participants will be asked to return unused drug and empty drug containers at each return visit. The Pharmacy Department at participating institutions will maintain a record of drugs dispensed for each participant.
Intervention code [1] 319466 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326233 0
The composite primary end point for metastatic NSCLC is disease control and it is defined as the objective tumour response, based on complete or partial response using cancer specific response criteria from RECIST v1.1 and/or RANO.. Where disease evaluation is not based on imaging scans (eg. CT), clinical assessment of response may be utilised. Response is assigned based on investigator discretion.
Timepoint [1] 326233 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first
Primary outcome [2] 326234 0
The composite primary end point for other cancers is disease control defined as: 1. Objective tumour response, based on complete and partial responses using cancer specific response criteria from RECIST v1.1 and/or RANO, or 2. Time to progressive (TTP) disease exceeds the documented time to progressive disease on the last treatment prior to substudy entry by at least 1.3 times (TTP2/TTP1 > 1.3). Or exceeds 6 months if TTP1 is not evaluable. Where disease evaluation is not based on imaging scans (eg. CT and MRI), biomarker-based or qualitative clinical assessment of response may be included, such as European Leukemia Net (ELN) guidelines for acute myeloid leukemia (AML), Gynecologic Cancer Intergroup (GCIG) and Prostate Cancer Working Group 3 (PCWG3) criteria will be employed. These data will be collected from participant questionnaires, such as quality of life per the QLQ-C30 version 3 or The Brief Pain Inventory, or clinical reports to supplement the primary outcome.
Timepoint [2] 326234 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.
Secondary outcome [1] 390631 0
Overall survival (OS) (death from any cause)
Timepoint [1] 390631 0
For the duration of the study. From the date of registration to date of death from any cause, or the date of last known follow-up alive.
Secondary outcome [2] 390632 0
Progression free survival (PFS). PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death from any cause, whichever occurs first. Participants who did not progress or die will be censored on the date of their last clinical assessment or tumour assessment. Disease progression is defined according to RECIST v1.1, RANO guidelines, or disease specific guidelines.
Timepoint [2] 390632 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.
Secondary outcome [3] 390633 0
Time to treatment failure. This is defined as the interval from the date of registration to date of permanently ceasing study treatment for any reason. The entered data in the trial database will be used to evaluate this outcome. Participants who are still on study treatment at time of analysis will be censored on the date of their last reported study treatment.
Timepoint [3] 390633 0
Time to treatment failure analysis is performed at 12 months from last patient registration.
Secondary outcome [4] 390634 0
Response duration according to RECIST 1.1
Timepoint [4] 390634 0
Imaging (eg. CT) scans for disease evaluation will take place every 8 weeks until disease progression or commencement of non-protocol anti-cancer therapy, whichever occurs first.
Secondary outcome [5] 390635 0
Progression Free Survival (PFS) at 6 months. PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death from any cause, whichever occurs first and is the proportion of participants on study who are alive and progression free at 6 months. The disease progression is defined according to RECIST v1.1, RANO guidelines, or disease specific guidelines.
Timepoint [5] 390635 0
At 6 months post participant registration via CT, MRI or PET (with CT function) scans of disease evaluation
Secondary outcome [6] 390636 0
Safety and tolerability of treatment (rates of adverse events). All adverse events (AEs), including event grading as per NCI CTCAE criteria, will be captured from the first dose of study treatment until 30 days after cessation of study treatment. Reported AEs (eg. diarrhoea, gastrointestinal disorder) by participants will be documented by study site staff and subsequently transcript onto study electronic data capturing (EDC) system. In order to evaluate the safety and tolerability of the study treatment, the entered AE types, frequency and severity in the EDC will be analysed.
Timepoint [6] 390636 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [7] 390637 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 and The Brief Pain Inventory Forms
Timepoint [7] 390637 0
Every 4 weeks from first dose of study treatment until end of treatment. Subsequently, at every 8 weeks until disease progression

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older, with either:
a. newly diagnosed metastatic non-squamous NSCLC identified through the ASPiRATION molecular screening program OR
b. advanced and/or metastatic solid cancer of any histologic type, refractory or unsuitable for standard therapies for that cancer type, identified through the MoST molecular screening program;
2. Harbouring a targetable ALK gene alteration identified using CGP and determined by the molecular tumour board. NSCLC patients who have an ALK gene alteration determined by IHC must be confirmed by NGS; Pan cancer patients who have ALK overexpression determined by IHC or rearrangement diagnosed by FISH must be confirmed by NGS;
3. NSCLC patients identified through the ASPiRATION molecular screening program must be FISH-negative, i.e. not eligible for PBS-reimbursed ALK-targeted treatment;
4. Confirmation of molecular eligibility by the molecular tumour board;
5. Measurable disease as assessed by RECIST 1.1 and/or RANO;
6. ECOG 0 to 2;
7. If the CNS is involved (either primary or metastatic disease), this must be asymptomatic or previously treated and controlled either with local treatment or by steroids; radiation treatment must be completed at least 14 days before enrolment and patients must be clinically stable;
8. Adequate organ system function as assessed by the following minimal laboratory requirements (within 7 days prior to first administration of study drug):
a. bone marrow function; platelets equal 100 x 109/L, ANC equal 1.5 x 109/L, and haemoglobin equal 90g/L (5.6mmol/L);
b. liver function; ALT/AST equal 3 x ULN (in the absence of liver metastases, equal 5 x ULN for patients with liver involvement) and total bilirubin equal 1.5xULN;
c. renal function; serum creatinine equal 1.5xULN;
9. Prior anticancer therapy:
a. For newly diagnosed metastatic, non-squamous NSCLC:
i. Up to 2 cycles of systemic therapy while awaiting the results of CGP testing are permitted (but not required);
b. For advanced and/or metastatic treatment-refractory solid cancer of any histologic type:
i. Participants must have received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists,
ii. Clinical or radiological progression on or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance,
iii. Patients previously treated with an ALK inhibitor (other than alectinib) are eligible, unless there is a known on-target resistant mutation (e.g. G1202R) or a compelling off-target resistance mechanism that is deemed unlikely to respond to alectinib, as determined by the MTB. The tumour sample must be obtained from a progression biopsy for genomic screening instead of the archival sample;
10. Life expectancy of at least 12 weeks
11. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
12. Signed, written informed consent to participation in the specific treatment substudy.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior ALK pathway inhibitor treatment;
2. Known history of hypersensitivity or contraindication to alectinib, or to any of the additives in the alectinib drug formulation;
3. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with alectinib, including:
a. GI disorder that may significantly affect absorption of oral medications, such as malabsorption syndromes or status post-major bowel resection
b. Symptomatic bradycardia
4. Co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol;
5. Treatment with any of the following anti-cancer therapies prior to the first dose of alectinib:
a. Radiation therapy, major surgery, or tumour embolization within 14 days prior to the first dose of study treatment. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions;
b. Any systemic therapy within 28 days prior to the first dose of alectinib;
6. Administration of any investigational treatment within 28 days prior to receiving the first dose of alectinib;
7. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g. hearing loss, peripheral neuropathy);
8. Prior or concurrent malignancy. History of another primary malignancy except for:
a. Malignancy treated with curative intent and with no known active disease within 2 years before consent to molecular screening and of low potential risk for recurrence;
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
c. Adequately treated carcinoma-in-situ without evidence of disease;
d. For participants with treatment-refractory solid tumours, a concurrent or past history of competing malignancy within 2 years, prior to molecular screening registration, is eligible, unless the competing malignancy is expected to lead to a shorter survival than the index malignancy;
9. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or agree to use a highly effective form of contraception. Women of childbearing potential must have a negative pregnancy test done within 3 days prior to registration. Men with partners of childbearing potential must have been surgically sterilised or agree to use a highly effective form 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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
A group of 16 participants harbouring ALK gene alterations will be recruited in this substudy of the Molecular Screening and Therapeutic trial (MoST). Substudies with 3/16 responding participants will, in general, be considered sufficiently interesting to investigate further. Due to the mixed nature of this 16 patient cohort, including first line lung cancer and late line pan cancer patients, outcomes will be reported descriptively and by relevant subgroup analyses

As described in the framework protocol (ACTRN12616000908437), substudies with greater than or equal to 3 out of 16 responding patients, will in general be sufficiently interesting to investigate further. As a general rule, substudies with less than 3 out of 16 responses will be considered to not support the molecular hypothesis behind the substudy.

If some activity is recognised in a 16 patient substudy cohort but further information is needed to inform development of phase II testing, Further substudies may be opened to enrich for patients that harbour a specific common biomarker or histologic cancer subtype. Each such iteration would constitute a new substudy for the purposes of this framework.

The sample size and guiding definitions of what constitutes an interesting signal are determined empirically as the investigators considered these numbers of patients as sufficient for signal-seeking purpose.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,VIC
Recruitment hospital [1] 18442 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 18443 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 18444 0
The Canberra Hospital - Garran
Recruitment hospital [4] 18445 0
The Prince Charles Hospital - Chermside
Recruitment hospital [5] 18446 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [6] 18447 0
Linear Clinical Research - Nedlands
Recruitment hospital [7] 18448 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [8] 18449 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [9] 18450 0
St George Hospital - Kogarah
Recruitment hospital [10] 18451 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 32550 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 32551 0
2065 - St Leonards
Recruitment postcode(s) [3] 32552 0
2605 - Garran
Recruitment postcode(s) [4] 32553 0
4032 - Chermside
Recruitment postcode(s) [5] 32554 0
4102 - Woolloongabba
Recruitment postcode(s) [6] 32555 0
6009 - Nedlands
Recruitment postcode(s) [7] 32556 0
3000 - Melbourne
Recruitment postcode(s) [8] 32557 0
5000 - Adelaide
Recruitment postcode(s) [9] 32558 0
2217 - Kogarah
Recruitment postcode(s) [10] 32559 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 307566 0
Government body
Name [1] 307566 0
Office for Health and Medical Research
Address [1] 307566 0
Locked Bag 961 North Sydney NSW 2059
Country [1] 307566 0
Australia
Funding source category [2] 307604 0
Other Collaborative groups
Name [2] 307604 0
OMICO - Outsmarting Cancer Together
Address [2] 307604 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [2] 307604 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 308252 0
None
Name [1] 308252 0
Address [1] 308252 0
Country [1] 308252 0
Other collaborator category [1] 281594 0
Other Collaborative groups
Name [1] 281594 0
OMICO - Outsmarting Cancer Together
Address [1] 281594 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [1] 281594 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307626 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 307626 0
Translational Research Centre, 97-105 Boundary Street, Darlinghurst NSW 2010
Ethics committee country [1] 307626 0
Australia
Date submitted for ethics approval [1] 307626 0
26/06/2020
Approval date [1] 307626 0
09/09/2020
Ethics approval number [1] 307626 0
2020/ETH01596

Summary
Brief summary
This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437. This substudy will evaluate the activity of alectinib in a population of participants with newly diagnosed metastatic non-squamous small cell lung cancer (NSCLC) or patients with advanced cancers harbouring ALK gene alterations identified using comprehensive genomic profiling (CGP).

Who is it for?
You may be eligible to join the study if you are aged 18 years and older, with pathologically confirmed advanced and/or metastatic NSCLC or solid tumour of any histologic type or an earlier diagnosis of a poor prognosis cancer. Your tumour will need to harbour ALK gene alterations identified using CGP.

Study details:
Participants will receive alectinib treatment. The alectinib is to be taken orally, at 600mg twice daily (days 1 to 28 in a 28-day treatment cycle).
Alectinib will be given to participants continuously as long as they and their doctor agree there is a benefit from treatment. Participants will undergo imaging assessments at 8 weekly intervals from first treatment until progression. Safety and tolerability of treatment will be assessed at 4 weekly intervals. Health related quality of life during treatment will be assessed at 4 weekly intervals and then every 8 weeks after end of treatment until progression.

We cannot guarantee that participants will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that Alectinib will be well tolerated and will improve outcomes for future patients, however, there may be no clear benefit from participation in this study.
Trial website
https://www.omico.com.au/about-us/our-programs/molecular-screening-therapeutics-most-study/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107910 0
Dr Malinda Itchins
Address 107910 0
Acute Services Building, L1
Royal North Shore Hospital,
Pacific Highway
St Leonards NSW 2062
Country 107910 0
Australia
Phone 107910 0
+61 2 8037 4100
Fax 107910 0
Email 107910 0
malinda.itchins@sydney.edu.au
Contact person for public queries
Name 107911 0
Dr Lucille Sebastian
Address 107911 0
NHMRC Clinical Trials Centre,
Medical Foundation Building,
Levels 4-6,
92-94 Parramatta Road,
Camperdown NSW 2050
Country 107911 0
Australia
Phone 107911 0
+61 2 9562 5000
Fax 107911 0
Email 107911 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 107912 0
Dr Malinda Itchins
Address 107912 0
Acute Services Building, L1
Royal North Shore Hospital,
Pacific Highway
St Leonards NSW 2062
Country 107912 0
Australia
Phone 107912 0
+61 2 9562 5000
Fax 107912 0
Email 107912 0
malinda.itchins@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans for this to occur at this time and participant consent is required for data sharing.
What supporting documents are/will be available?
No other documents available
Summary results
No Results