Proof of concept trial alternating lorlatinib with crizotinib in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer
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
Royal North Shore Hospsital
25 participants
Jun 14, 2019
Interventional
Conditions
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.
Eligibility
Inclusion Criteria14
- Adults aged >=18 years with pathologically confirmed stage IV ALK gene rearranged NSCLC (predominately adenocarcinoma phenotype) 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 systemic therapy, provided the most recent ALKi was a second generation agent
- Extracranial RECIST measurable disease confirmed =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 >=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, Hb =90)
- Adequate liver function (e.g. ALT/AST < = 3 x ULN; if liver metastases <= 5 x ULN, bilirubin <= 2 x ULN)
- Adequate renal function (e.g. creatinine clearance >= 50 ml/min, serum creatinine <= 1.5 x ULN)
- 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
Exclusion Criteria21
- Most recent systemic treatment is crizotinib
- Prior hypersensitivity to crizotinib
- Primary resistance to first line ALKi therapy (first or second generation ALKi)
- Prior lorlatinib therapy or other third generation ALKi therapy
- Prior toxicity to crizotinib contraindicating further use
- Previous ALKi therapy within 4 days, or chemotherapy or radiotherapy within 7 days
- 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
- Significant cardiac dysfunction
- Untreated and or non-clinically stable symptomatic CNS including leptomeningeal disease
- Past history of malignancy except the following whom are eligible: 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. Patients with a history of other malignancies 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
- 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 (Section 8.6)
- 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
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Interventions
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.
Locations(2)
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ACTRN12619000844145