None listed
Conditions
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.
Interventions
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 dru
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.
Sponsors
The University of Sydney
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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 or 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 7. Life expectancy greater than or equal to 3 months 8. ECOG performance status 0 or 1
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
Outcome results
None listed