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Trial registered on ANZCTR


Registration number
ACTRN12619000844145
Ethics application status
Approved
Date submitted
29/05/2019
Date registered
13/06/2019
Date last updated
11/07/2019
Date data sharing statement initially provided
13/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Proof of concept trial alternating lorlatinib with crizotinib in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer
Scientific title
A single arm multi-centre translational proof of concept study investigating the safety and efficacy of alternating lorlatinib with crizotinib in a pre-treated advanced ALK-rearranged non-small cell lung cancer population with disease progression on a 2nd generation ALK tyrosine kinase inhibitor
Secondary ID [1] 298344 0
None
Universal Trial Number (UTN)
Trial acronym
ALKternate
Linked study record

Health condition
Health condition(s) or problem(s) studied:
ALK-rearranged advanced non-small cell lung cancer 312994 0
Condition category
Condition code
Cancer 311501 311501 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Lorlatinib 100mg once daily for 3 months (Cycle 1, induction phase) and if disease control the below:

Crizotinib 250 mg morning and night for 4 weeks then lorlatinib 100 mg daily for 8 weeks (Cycle 2), and continue alternating (i.e. alternating 4 weekly cycles of each crizotinib then 8 weeks of lorlatinib) until disease progression or unacceptable toxicity (Alternating Phase). A 48 hour drug free interval in between alternating drug therapy will occur based on pharmacokinetic drug-drug interaction considerations. Imaging including MRI-B and CT CAP will be performed more frequently than standard practice with the first two Cycles of Alternating therapy, undertaken at each drug switch to ensure safety and ongoing disease control.

Following disease progression and if deemed appropriate by the treating Investigator, continuation of alternating therapy OR continuous lorlatinib until further progression or unacceptable toxicity may be permitted (Post-Progression Phase).

Both crizotinib and lorlatinib will be supplied as tablets for oral administration. Adherence will be monitored by counting returned empty drug packets.
Intervention code [1] 314588 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320211 0
Time to treatment failure (TTTF) with alternating ALKi therapy (according to Response Evaluation Criteria in Solid Tumours [RECIST] v1.1)
Timepoint [1] 320211 0
TTTF is defined as the time in months from treatment initiation to treatment discontinuation for any reason at investigator discretion, including disease progression, treatment toxicity, patient preference, clinical deterioration or death.

Patients will be assessed clinically monthly with bloods, and radiologically via a CT CAP and MRI-B at 3 months after Induction, and then more frequently with the first two cycles of Alternating therapy, occurring with each drug switch timepoint to ensure safety and disease control. From Cycle 3 Alternating thereafter, imaging will occur three monthly.
Secondary outcome [1] 370872 0
Best objective tumour response rate (ORR) at any time on study, defined as the proportion of participants with a confirmed complete or partial response according to RECIST v1.1
Timepoint [1] 370872 0
Patients will be assessed clinically monthly with bloods. Radiological response will be assessed via a CT CAP and MRI-B as per study schedule of imaging, first at 3 months, then +1 month, then +2 months, then +1 months then +2 months (eg. every drug switch for Cycle 1 and 2 of the Alternating Phase), before 3 monthly thereafter from the time of enrollment until disease progression. Imaging reports will be in accordance with Response Evaluation Criteria in Solid Tumours (RECIST v1.1).
Secondary outcome [2] 370873 0
Progression free survival (PFS, disease progression or death)
Timepoint [2] 370873 0
Patients will be assessed clinically monthly with bloods. Radiological disease control will be assessed in accordance with Response Evaluation Criteria in Solid Tumours (RECIST v1.1) and as per study schedule of imaging, first at 3 months, then +1 month, then +2 months, then +1 months then +2 months (eg. every drug switch for Cycle 1 and 2 of the Alternating Phase), before 3 monthly thereafter from the time of enrollment until disease progression.
Secondary outcome [3] 370874 0
Overall DCR (CR, PR, SD; systemic and CNS) % after 3 months lorlatinib induction and after the first Cycle of Alternating therapy and the Median DCR
Timepoint [3] 370874 0
Clinical benefit will be assessed according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) guidelines via CT-CAP and MRI-B. Patients will be assessed clinically monthly with bloods. Radiological disease control will be assessed as per study schedule of imaging, first at 3 months, then +1 month, then +2 months, then +1 months then +2 months (eg. every drug switch for Cycle 1 and 2 of the Alternating Phase), before 3 monthly thereafter from the time of enrollment until disease progression.
Secondary outcome [4] 370875 0
Overall survival (death from any cause), collected prospectively on study.
Timepoint [4] 370875 0
Patient status updates will be sought every 4 weeks at clinic visit whilst on trial and then y every 8-12 weeks after study until death.
Secondary outcome [5] 370876 0
Safety and Toxicity (Adverse events graded according to NCI CTCAE Version 4.03, and Pharmacokinetic (PK) Analysis)

Examples of Known and possible adverse events are listed below-

Lorlatinib:

Common (affects 1-in-10 to 5+-in-10 patients)

• Diarrhoea
• Swelling of the extremities
• High lipids (high levels of fat in the blood)
• Peripheral nerve changes
• Change in mood
• Weight gain
• Joint aches

Less common (affects less than 1-in-10 patients)

• Abnormal liver blood tests
• Nausea/Vomiting
• Rash
• Speech effects
• Breathing problems

Crizotinib:

Common (affects 1-in-10 to 5+-in-10 patients)

• Temporary visual disturbance (your doctor will further explain potential effects)
• Diarrhoea
• Tiredness
• Swelling of the peripheries
• Nausea/vomiting/Decreased appetite
• Constipation
• Abnormal liver blood tests
• Abdominal pain
• Altered taste
• Headaches
• Peripheral nerve changes


Less common (affects less than 1-in-10 patients)

• Low blood counts for example low red and white cells
• Dizziness
• Breathlessness
Timepoint [5] 370876 0
Adverse events will be reported at baseline and assessed 4 weekly whilst on study treatment and at the end of treatment study visit. Clinical history, examination, routine bloods, ECG will be reviewed every clinic visit from baseline, D15 of cycle 1 and week 4, then 4 weekly thereafter.

PK blood draw will occur between cycle 1-2a and cycle 2a-2b at drug switch (two time points). Drug will be stopped 48 hours prior to the start of a new cycle and drug switch. Bloods will be drawn at 1, 2, 4, 6 and 24 hours post taking the new cycle oral drug.

Secondary outcome [6] 370877 0
Patient-rated quality of life (PRO) assessment
Timepoint [6] 370877 0
Patient rated quality of life will be assessed via self-report questionnaires (FACT-L survey) at baseline and every 4 weeks thereafter until disease progression.
Secondary outcome [7] 370878 0
Mechanisms of resistance in patients progressing on alternating lorlatinib and crizotinib as identified in ctDNA or plasma proteins - Exploratory outcome
Timepoint [7] 370878 0
Patient plasma will be collected at baseline; week 12 then with each drug switch thereafter with a final collection at end of study. A mandated tissue biopsy will be performed at trial entry and at disease progression if deemed clinically safe and feasible. Based on PFS data, time points of interest will be identified and analysed post hoc.

Eligibility
Key inclusion criteria
• Adults aged 18 years or older with pathologically confirmed stage IV ALK gene rearranged NSCLC by IHC and or FISH, fresh or archival, not required to be reconfirmed centrally
• Confirmed radiological disease progression on prior second generation ALKi as per RECIST Version 1.1
• Any prior number of lines of therapy, provided the most recent ALKi was a second generation agent, however this does not need to be the most recent line of therapy
• Previous ALKi therapy not within 4 days, or chemotherapy or radiotherapy not within 7 days
• Extracranial RECIST measurable disease confirmed no longer than 28 days prior to start of study
• Eastern Co-operative Oncology Group (ECOG) performance status =1
• Patients with asymptomatic CNS disease including leptomeningeal disease are eligible
• Patients with symptomatic CNS disease including leptomeningeal disease are eligible if treated with local therapy(ies) including surgery and or radiotherapy and stable clinically with stable steroid requirements for at least 14 days
• Patients with oligo-progression in the CNS are eligible, provided they meet criteria above
• Adequate bone marrow function (e.g. platelets > 100 x 109/L, ANC 1.5 x 109/L or above, Hb 90 or above)
• Adequate liver function (e.g. ALT/AST no greater than 3 x ULN; if liver metastases no greater than 5 x ULN, bilirubin no greater than 2 x ULN)
• Adequate renal function (e.g. creatinine clearance at least 50 ml/min)
• Adequate cardiac function (e.g. ECG and echocardiogram if clinically indicated)
• Hepatitis B and C infection if controlled on anti-virals
• Study treatment both planned and able to start within 14 days of registration
• Willing and able to comply with all study requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments (e.g. able to have IV contrast if this is required for tumour assessments)
• Signed, written informed consent (for trial inclusion and tissue collection)
• Prior screen failure patients are eligible for rescreening
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Most recent systemic treatment not a second generation ALK inhibitor
• Prior hypersensitivity to crizotinib or toxicity contraindicating further use
• Prior lorlatinib therapy
• Specific comorbidities or conditions affecting compliance to clinical trial
• Life expectancy of less than 3 months
• Inability to tolerate or contraindication to MRI-B imaging
• No measurable disease via RECIST criteria extra-cranially
• Untreated and or non-clinically stable symptomatic CNS including leptomeningeal disease
• Patients with a history of malignancy are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment, with the exception of men with prostate cancer, eligible if PSA and radiological control for at least 2 years. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial transitional cell carcinoma of the bladder, or curatively treated cervical carcinoma in situ are eligible at any time from diagnosis.
• Significant uncontrolled infection, including chronic active hepatitis B, hepatitis C, or HIV.
• Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
• The requirement to continue one of the excluded concomitant medications
• Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol
• Comorbid malabsorption syndrome or other gastrointestinal (GI) illness or condition that could affect oral absorption of the study drug
• Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse
• 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
• An inability to travel to the enrolled site to participate in the trial and all required visits

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 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A total sample size of 25 participants are required, accounting for early drop off, to enable at least 20 patients to enter the Alternating ‘active’ phase of the clinical trial. Only patients in the Alternating phase will be included in the analysis. Results from patients treated with continuous lorlatinib beyond progression will be reported separately.

The sample size has been chosen based on a scientific estimate of the number of patients required to capture a representative cohort in a rare tumour including those with CNS disease and to enable a signal to carry forward further investigation in an expanded cohort.

Descriptive statistics will be used to report ORR and safety. The Kaplan Meier Method will be used to report PFS and OS.

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)
NSW,VIC
Recruitment hospital [1] 13830 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 13831 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 26591 0
2065 - St Leonards
Recruitment postcode(s) [2] 26592 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 302890 0
Commercial sector/Industry
Name [1] 302890 0
Pfizer
Address [1] 302890 0
Level 15/18, 151 Clarence St, Sydney NSW 2000

Country [1] 302890 0
Australia
Funding source category [2] 302896 0
Charities/Societies/Foundations
Name [2] 302896 0
Fight for a Cure
Address [2] 302896 0
16/101 Miller Street, North Sydney, NSW, Australia 2060
Country [2] 302896 0
Australia
Primary sponsor type
Hospital
Name
Royal North Shore Hospsital
Address
Northern Sydney Cancer Centre, Reserve Rd, St Leonards, NSW, Australia 2065
Country
Australia
Secondary sponsor category [1] 302850 0
Hospital
Name [1] 302850 0
Peter MacCallum Cancer Centre
Address [1] 302850 0
305 Grattan St, Melbourne VIC 3000
Country [1] 302850 0
Australia
Other collaborator category [1] 280712 0
Other Collaborative groups
Name [1] 280712 0
Australasian Lung Cancer Trials Group
Address [1] 280712 0
Level 2, 11 Finchley Street Milton QLD 4064
Country [1] 280712 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303459 0
Northern Sydney Local Health District HREC
Ethics committee address [1] 303459 0
Level 13 Kolling Building
Royal North Shore Hospital
St Leonards NSW 2065
Ethics committee country [1] 303459 0
Australia
Date submitted for ethics approval [1] 303459 0
25/02/2019
Approval date [1] 303459 0
08/04/2019
Ethics approval number [1] 303459 0
ETH00389

Summary
Brief summary
The primary purpose of this trial is to evaluate the efficacy, safety and feasibility of alternating lorlatinib and crizotinib for the treatment of ALK-rearranged advanced non-small cell lung cancer.

Who is it for?
You may be eligible to enrol in this trial if you are aged 18 or over and have been diagnosed with ALK-rearranged advanced non-small cell lung cancer, refractory to prior therapy(ies).

Study details
All participants enrolled in this trial will begin with Induction therapy which involves taking lorlatinib tablets every day for 12 weeks. Participants will then move onto the Alternating phase. During the Alternating phase participants will take crizotinib for 4 weeks, then lorlatinib for 8 weeks, then crizotinib for another 4 weeks, and lorlatinib for 8 weeks until disease progression or unacceptable side effects. Following progression, some participants may be eligible to continue with alternating treatment or switch to continuous lorlatinib treatment until further progression, depending on whether your doctor believes that this would be of benefit to you.

All patients will be reviewed up to every four weeks clinically, with bloods tests, CT scan and MRI (brain) and side effect assessments.

It is hoped that the findings from this trial will provide information on whether alternating treatment with crizotinib and lorlatinib is feasible, safe and effective for the treatment of ALK-rearranged advanced non-small cell lung cancer with the potential to delay the emergence of drug resistance as compared to continuous lorlatinib therapy alone.
Trial website
Trial related presentations / publications
Public notes
Trial in Progress Abstract to be Presented at IASLC World Conference on Lung Cancer (WCLC) Sep 2019, Abstract 2043.
Type: Peer Review
Topic: Advanced NSCLC
Title: ALKternate: A Proof of Concept Study in ALK-Rearranged NSCLC Alternating Lorlatinib with Crizotinib After Disease Progression
Authors: M. Itchins, S. Hayes, A. Hudson, V. Howell, S.W.D. Tan, S. Clarke, B. Solomon, N. Pavlakis

Contacts
Principal investigator
Name 93730 0
A/Prof Nick Pavlakis
Address 93730 0
Department of Medical Oncology
Royal North Shore Hospital
Reserve Road, St Leonards
New South Wales, Australia 2065
Country 93730 0
Australia
Phone 93730 0
+61 2 9463 1172
Fax 93730 0
+61 2 9463 1092
Email 93730 0
nick.pavlakis@sydney.edu.au
Contact person for public queries
Name 93731 0
Dr Malinda Itchins
Address 93731 0
Department of Medical Oncology
Royal North Shore Hospital
Reserve Road, St Leonards
New South Wales, Australia 2065
Country 93731 0
Australia
Phone 93731 0
+61 2 99264722
Fax 93731 0
+61 2 99264035
Email 93731 0
malinda.itchins@sydney.edu.au
Contact person for scientific queries
Name 93732 0
Dr Malinda Itchins
Address 93732 0
Department of Medical Oncology
Royal North Shore Hospital
Reserve Road, St Leonards
New South Wales, Australia 2065
Country 93732 0
Australia
Phone 93732 0
+61 2 99264722
Fax 93732 0
+61 2 99264035
Email 93732 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
Permission from patients are not sought in the participant information and consent form.
What supporting documents are/will be available?
No other documents available
Summary results
No Results