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Trial registered on ANZCTR


Registration number
ACTRN12620000568910p
Ethics application status
Submitted, not yet approved
Date submitted
4/05/2020
Date registered
15/05/2020
Date last updated
15/05/2020
Date data sharing statement initially provided
15/05/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 10 substudy 23-24: Palbociclib and Avelumab
Scientific title
Single arm, open label, signal seeking, phase II trial of the activity of Palbociclib in combination with Avelumab in patients with tumours with amplified D-type cyclins or CDK4/6 or inactivation of CDKN2A.
Secondary ID [1] 301184 0
CTC0141-addendum 10
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 10
Linked study record
This record is an addendum to the MoST framework protocol (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 is linked to ACTRN12616000908437.

Health condition
Health condition(s) or problem(s) studied:
Cancer 317329 0
Condition category
Condition code
Cancer 315438 315438 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Palbociclib will be given first on its own in the first cycle of treatment. Palbociclib is taken orally by participants at home at a dose of 125 mg once daily for 21 days, followed by 7 days of washout. The Palbociclib dosage may be reduced to 100 mg or 75 mg once daily if participant experiences intolerance toxicity. 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.

Avelumab will be administered intravenously at a dose of 10 mg/kg every 2 weeks, starting from the second cycle of treatment.

Both palbociclib and avelumab will be administered continuously until disease progression is documented or when the participant experiences intolerable toxicity or withdraws for another reason.
Intervention code [1] 317492 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 323690 0
The primary end point is the progression-free survival at 6 months (PFS6)). 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, iRECIST, or RANO guidelines. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be considered to have progressed at the time of commencement of subsequent therapy.
Timepoint [1] 323690 0
CT or MRI scans for disease evaluation will take place every 8 weeks for the first 24 weeks, and then every 12 weeks until disease progression.
Secondary outcome [1] 382596 0
Progression free survival (PFS). Disease progression is defined according to RECIST v1.1, iRECIST, and RANO guidelines.
Timepoint [1] 382596 0
CT or MRI scans for disease evaluation will take place every 8 weeks for the first 24 weeks, and then every 12 weeks until disease progression.
Secondary outcome [2] 382597 0
Objective tumour response (OTR), based on complete and partial responses using cancer specific response criteria.Disease progression is defined according to RECIST v1.1, iRECIST, or RANO guidelines.
Timepoint [2] 382597 0
CT or MRI scans for disease evaluation will take place every 8 weeks for the first 24 weeks, and then every 12 weeks until disease progression.
Secondary outcome [3] 382598 0
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 CT scans alternative validated guidelines, such as Gynecologic Cancer Intergroup (GCIG) and Prostate Cancer Working Group 2 (PCWG2) criteria will be employed. Where radiological progression cannot be assessed, evidence for clinical progression will be documented. 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 [3] 382598 0
CT or MRI scans for disease evaluation will take place every 8 weeks for the first 24 weeks, and then every 12 weeks until disease progression.
Secondary outcome [4] 382599 0
Overall survival (OS) (death from any cause).
Timepoint [4] 382599 0
For 12 months or when the treatment ceased (if less than 12 months).
Secondary outcome [5] 382600 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. AEs reported by participants will be documented by study site staff and subsequently transcribed 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 [5] 382600 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [6] 382601 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 and The Brief Pain Inventory Forms.
Timepoint [6] 382601 0
Every 8 weeks for the first 6 months and then every 12 weeks until disease progression.

Eligibility
Key inclusion criteria
Inclusion Criteria – molecular screening:
1. Male or female patients, aged 18 years and older, with pathologically confirmed advanced and/or metastatic cancer of any histologic type, including haematological cancers, or an earlier diagnosis of a poor prognosis cancer;
2. Sufficient and accessible tissue for molecular screening;
3. Patients receiving their last line of standard treatment or who have received and failed all standard anticancer therapy (where standard therapy exists) or have documented unsuitability for any further standard anticancer therapy. Poor prognosis cancers or cancers with low expected response rate to standard treatment (in the opinion of the investigator and based on available evidence) may be screened on an earlier line of treatment.
a. Failure is defined as either progression of disease (clinical or radiological) or intolerance to standard therapy resulting in the discontinuation of the therapy.
b. Documented unsuitability for further standard therapy includes known hypersensitivity, organ dysfunction or other patient factors that would make therapy unsuitable in the judgement of the responsible investigator;
4. ECOG performance status 0, 1 or 2;
5. Willing and potentially able to comply with study requirements, including treatment, timing and/or nature of required assessments; It is the intention to screen patients who are in principle wishing to take part in a MoST substudy if they are found to have an appropriate tumour biomarker and are still eligible for enrolment at the time of the treatment phase;

It is the intention to screen patients who are in principle wishing to take part in a MoST substudy if they are found to have an appropriate tumour biomarker and are still eligible for enrolment at the time of the treatment phase (substudy).

To be eligible for treatment in a substudy, patients must continue to meet all of the inclusion criteria and none of the exclusion criteria specified for entry into molecular screening at the time of registration to a treatment substudy. In addition, they must meet all the inclusion criteria and none of the exclusion criteria in the substudy addendum at the time of registration.

Inclusion Criteria – substudy:
1. Confirmation of molecular eligibility by the molecular tumour board; Patients with tumour harbouring
a. Gain-of-function mutations in CDK4 and CCND1-3
b. CDKN2A deletion or loss-of-function mutations
2. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists;
3. Clinical or radiological progression on or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance;
4. 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 or greater than 100 x 10^9/L, ANC equal or greater than 1.5 x 10^9/L, and haemoglobin equal or greater than 9g/dL (5.6mmol/L); This will not apply for patients with haematological cancers if cytopenias are disease related;
b. liver function; ALT/AST equal or less than 3 x ULN (in the absence of liver metastases, equal or less than 5 x ULN for patients with liver involvement) and total bilirubin equal or less than 1.5xULN;
c. renal function; serum creatinine equal or less than 1.5xULN;
5. Measurable disease by iRECIST and RECIST v 1.1 or RANO
6. Consent to have a fresh core biopsy at end of cycle 1 of study treatment
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusions criteria - molecular screening
1. Suitable for standard therapy or accepted standard care, if the patient has not been previously treated;
2. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may contraindicate participation and/or interact with the investigational product;
3. Other 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;
4. For non central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer are excluded. Subjects with stable neurological function on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to screening are eligible;
5. History of another malignancy within 2 years prior to molecular screening registration are excluded unless adequately treated and determined free of progressive and metastatic disease for at least 6 months. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder can be included;
6. Pregnancy, lactation or inadequate contraception.

Exclusion criteria - substudy
1. Hormone positive breast cancer
2. Contraindications to investigational product;
3. Known history of hypersensitivity to active or inactive components of investigational product;
4. Prior treatment with CDK4/6 inhibitor or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway
5. Prior treatment with checkpoint inhibitor
6. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers, and drugs that are known to prolong the QT interval
7. QTc interval greater than 480 msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
8. Prolonged use of moderate to high doses of immunosuppressive medication before the first dose of avelumab. Exceptions include intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses (eg. <=10 mg/day of prednisone; use of dexamethasone up to 4mg /day within 14 days of initial treatment for patients with brain tumours).
9. Receipt of any organ transplantation including allogeneic stem-cell transplantation.
10. Significant acute or chronic infections including, among others:
a. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
b. Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive)
11. Active or history of any autoimmune disease (subjects with diabetes Type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible) or immunodeficiencies.
12. Currently diagnosed with interstitial lung disease or pneumonitis
13. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s);
14. 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;
15. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
a. Radiation therapy, 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. Chemotherapy, biologic therapy, or hormonal therapy within 14 days or 5 half-lives of a drug prior to the first dose of study treatment or until recovery from previous therapy (whichever is longer);
16. Any unresolved toxicity ( greater than 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);
17. Administration of any investigational treatment within 30 days

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)
Statistical methods / analysis
A group of 32 patients will be recruited for 2 substudies containing 16 subjects each. Subjects in group 1 will have tumours with gain-of function mutations in CDK4 and CCND1-3 and subjects in group 2 will have tumours with CDKN2A deletion or loss-of-function mutations.

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, iterative 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
Not yet 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,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 305633 0
Government body
Name [1] 305633 0
Office for Health and Medical Research
Address [1] 305633 0
Locked Bag 961 North Sydney NSW 2059
Country [1] 305633 0
Australia
Funding source category [2] 305634 0
Other Collaborative groups
Name [2] 305634 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [2] 305634 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [2] 305634 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 306040 0
None
Name [1] 306040 0
Address [1] 306040 0
Country [1] 306040 0
Other collaborator category [1] 281299 0
Other Collaborative groups
Name [1] 281299 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [1] 281299 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [1] 281299 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 305922 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 305922 0
Translational Research Centre, 97-105 Boundary Street, Darlinghurst NSW 2010
Ethics committee country [1] 305922 0
Australia
Date submitted for ethics approval [1] 305922 0
27/04/2020
Approval date [1] 305922 0
Ethics approval number [1] 305922 0

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 combination of palbociclib and avelumab after initial priming with palbociclib in patients with advanced cancer with eligible mutations of the following:
1. Gain-of function mutations in CDK4 and CCND1-3
2. CDKN2A deletion or loss-of-function mutations

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 solid cancer of any cell type or an earlier diagnosis of a poor prognosis cancer and have received all standard anticancer therapy. Participants will have tumours with gain-of function mutations in CDK4 and CCND1-3, or CDKN2A deletion or loss-of-function mutations.

Study details
Participants will receive palbociclib on its own in the first cycle. Palbociclib will be taken orally at a dose of 125 mg once daily for 21 days, followed by 7 days of washout. Participants will then start to receive avelumab at a dose of 10 mg/kg every 2 weeks from the second cycle of treatment. Both palbociclib and avelumab 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 for the first 24 weeks and then every 12 weeks 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 8 weekly intervals for the first 24 weeks and then every 12 weeks until progression.

We cannot guarantee that patients 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 T-DM1 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
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102074 0
Prof David Thomas
Address 102074 0
Garvan Institute of Medical Research The Kinghorn Cancer Centre 370 Victoria St Darlinghurst NSW 2010
Country 102074 0
Australia
Phone 102074 0
+61 2 9355 5770
Fax 102074 0
+61 2 9355 5872
Email 102074 0
d.thomas@garvan.org.au
Contact person for public queries
Name 102075 0
Dr Lucille Sebastian
Address 102075 0
NHMRC Clinical Trials Centre, Medical Foundation Building Levels 4-6, 92-94 Parramatta Road, Camperdown NSW 2050
Country 102075 0
Australia
Phone 102075 0
+61 2 9562 5000
Fax 102075 0
Email 102075 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 102076 0
Prof David Thomas
Address 102076 0
Garvan Institute of Medical Research The Kinghorn Cancer Centre 370 Victoria St Darlinghurst NSW 2010
Country 102076 0
Australia
Phone 102076 0
+61 2 9355 5770
Fax 102076 0
+61 2 9355 5872
Email 102076 0
d.thomas@garvan.org.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