This trial is a multicenter, open-label, biology driven, phase II study using a sequential
Bayesian design, aiming to assess the efficacy and safety of different Matched Targeted
Therapy (MTT) in independent and parallel cohorts of treatment.
Patients will be assigned to a treatment cohort based on molecular
alterations/characteristics detected on tumor sample from primary tumor or metastatic lesion.
In this protocol, several MTTs treatment cohorts are planned. This study is designed with the
flexibility to open new MTTs treatment cohorts and to close existing MTTs treatment cohorts
that demonstrate no clinical benefit. Each treatment cohort will be driven separately even
though procedures, quality control and reporting, will be common. The protocol will be
amended in order to include new treatments or combinations that emerge as being of interest
for patients with advanced/metastatic cancers.
All eligible patients will receive study drugs as long as patient experiences clinical
benefit in the opinion of the investigator, or until unacceptable toxicity, or until
symptomatic deterioration attributed to disease progression as determined by the investigator
after an integrated assessment of radiographic data and clinical status, or withdrawal of
Patients will be permitted to continue study treatment after progressive disease according to
RECIST v1.1 if they meet all of the following criteria and following validation of the
- Evidence of clinical benefit as assessed by the investigators,
- Absence of symptoms and signs (including worsening of laboratory values; e.g., new or
worsening hypercalcemia) that indicate unequivocal progression of disease,
- No decline in ECOG Performance Status (PS) that can be attributed to disease
- Male or female patients aged of at least 18 years on day of signing informed consent.
- Patients with histologically confirmed diagnosis of metastatic disease or unresectable
locally advanced malignancy that is resistant or refractory to standard therapies or
for which standard therapies does not exist or is/are not considered appropriate by
- A multidisciplinary molecular board must have recommended the specific MTT based on
the following documented actionable alterations: amplification of CDK6 and/or CDK4,
and/or CDKN2A homozygous deletion, and/or amplification of CCND1 and/or CCND3 with no
deletion/losses more than single copy of RB1 by copy number and P53 wild-type.
- Previously treated by at least one prior line of treatment in the advanced/metastatic
- Documented radiological disease progression as per RECIST v1.1 and presence of at
least one measurable lesion according to RECIST 1.1 criteria based on screening tumor
- Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group
- Adequate organ function, all screening laboratory tests should be performed within 7
days prior to Cycle 1 Day 1 (C1D1) :
- Hematological (without transfusion within 14 days prior to screening lab tests) :
- Absolute neutrophil count (ANC) ≥ 1.5 G/L,
- Platelets ≥ 100 G/L,
- Hemoglobin ≥ 9 g/dL,
- Lymphocyte count ≥ 0.8 G/L,
- White blood cell count ≥ 3 G/L.
- Renal and Hepatic function :
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 × Upper
Limit of Normal (ULN) in the absence of liver metastases (or ≤ 5 × ULN in case of
liver metastasis or hepatic infiltration),
- Serum total bilirubin ≤ 1.5 × ULN (except for patients with Gilbert disease for
whom a total serum bilirubin ≤ 3 x ULN is acceptable),
- Serum creatinine ≤ 1.5 × ULN or Creatinine clearance ≥ 50 mL/min/1.73m2
calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
- Adequate ionic balance: potassium, calcium, magnesium and phosphorus within
normal limits (supplementation is authorized)
- Adequate cardiovascular function :
- corrected QT interval by Fredericia (QTcF) ≤ 450 ms,
- Resting blood pressure systolic < 160 mmHg and diastolic < 90 mmHg,
- Heart rate > 50 bpm at rest,
- Left Ventricular Ejection Fraction (LVEF) ≥ 50% as determined by Multi Gated
Acquisition scan (MUGA Scan) or transthoracic echocardiogram.
- Specific toxicities related to any prior anti-cancer therapy must have resolved to
grade ≤1 , except for alopecia (all grades), grade 2 neuropathy or anemia.
- Unless documented infertility, men must agree to use effective contraception from C1D1
until 21 days after the last dose of study drugs.
- Women of child-bearing potential must have a negative serum pregnancy test within 7
days of first dose of study drugs and agree to use effective contraception from the
date of negative pregnancy test to up to 21 days after the last dose of study drugs.
- Patient should understand, sign, and date the written voluntary informed consent form
prior to any protocol-specific procedures performed. Patient should be able and
willing to comply with study procedures as per protocol.
- Patient must be covered by a medical insurance.
- Patients amenable to therapy with curative intent.
- Patients participating to another clinical trial with a medicinal product.
- Patients previously treated with similar MTT meaning any agent targeting the same
signaling pathways components.
- Patients unable to swallow oral medication.
- Patients with known hypersensitivity to Ribociclib excipients: hypersensitivity to
peanut or soy.
- Patients with symptomatic central nervous system (CNS) metastasis who are
neurologically unstable or require increasing doses of corticosteroids or local
CNS-directed therapy to control their CNS disease.
- Patients with secondary malignancy unless this malignancy is not expected to interfere
with the evaluation of study endpoints and is approved by the sponsor. Examples of the
latter include: basal or squamous cell carcinoma of the skin, in-situ carcinoma of the
cervix, localized prostate cancer, prior malignancy and no evidence of recurrence for
≥ 2 years.
- Patients using, or requirement to use while on the study, or not respecting the
minimal wash-out period of medications listed below:
- Any approved anti-cancer treatment Or Any investigational therapy other than the
specified therapies in present protocol (4 weeks)
- Chemotherapy 4 weeks (6 weeks for nitrosoureas and mitomycin C).
- Radiotherapy 4 weeks
- Surgery : Major surgical procedure, open biopsy, or significant traumatic injury
- Live vaccines 4 weeks
- Growth factors targeting the myeloid lineage 2 weeks
- Medicinal products known to prolong the QT interval and/ or to induce "Torsades
de Pointes" 1 week
- Strong and moderate inducers or inhibitors of CYP3A4/5, CYP3A4/5 substrates with
a narrow therapeutic index 1 week
- Substrates of CYP2C19 with a narrow therapeutic index and Substrates of OATP1B1
prohibited 24 hours prior and 1 week after HDM201 administration
- Substrates of P-gp prohibited 4 hours before and after HDM201 and Ribociclib
- Patients with history of thromboembolic or cerebrovascular events within the last 3
months, including transient ischemic attack, cerebrovascular accident, deep vein
thrombosis, or pulmonary embolism.
- Patients with clinically significant, uncontrolled heart disease and/or recent events
including any of the following:
- History of acute coronary syndromes or symptomatic pericarditis within 12 months
prior to C1D1,
- History of documented congestive heart failure,
- Documented cardiomyopathy,
- History of any cardiac arrhythmias, e.g. ventricular, supraventricular, nodal
arrhythmias, or conduction abnormality within 12 months prior to C1D1,
- Congenital long QT syndrome or family history of long QT syndrome,
- Patients with drug eluting stents for cardiovascular purposes.
- Patients with a diagnosis of acute or chronic pancreatitis.
- Impairment of gastrointestinal function or GI disease that may significantly alter
drug absorption of oral drugs
- Known Human Immunodeficiency Virus (HIV) infection and/or active Hepatitis B (HBV) or
Hepatitis C (HCV) infection.
- Any clinically significant and/or uncontrolled medical disease that could compromise
the patient's ability to tolerate study drug or would likely interfere with study
procedures or results.
- Patients with known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Patients who are pregnant or breastfeeding women or expecting to conceive or father
children within the projected duration of the trial, starting with the screening visit
through 21 days after the last dose of trial treatment.