MoST 10 (substudies 23-24): This Phase II trial is evaluating how safe, tolerable and effective targeted therapy (palbociclib) is when combined with immunotherapy (avelumab) is in people with solid cancers with activating alterations in cell cycle genesSingle 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.

Inclusion

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