futilty of the treatment

The study consists of two distinct and sequential parts:

• A Phase Ib aimed at determining the MTD (Maximum Tolerated Dose) of the combination (copanlisib/cetuximab) and the RP2D
• A Phase II aimed at evaluating the efficacy of the combination at the RP2D (Recommended Phase 2 Dose)

All patients will be treated with the Copanlisib, a selective PI3KCA inhibitor, in association with Cetuximab.

Inclusion Criteria:

1. Patients with R/M HNSCC (oropharynx, oral cavity, hypopharynx and larynx), histologically or cytologically confirmed, not amenable to curative treatment with surgery and/or chemotherapy and/or radiotherapy (Stage III/IV)

2. Adult men and women ≥ 18 years

3. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2

4. Patients with tumor harboring a PI3K mutation/amplification and/or a PTEN loss

5. Patients with a radiologic documented progression or relapse after cetuximab therapy (patients could have either received combination platinum doublet with cetuximab or cetuximab after platinum doublet)

6. Patients with prior platinum based therapy, unless contraindicated

7. Patients with at least one measurable lesion assessed by Magnetic Resonance Imaging (MRI) or a computerized tomography scanner (CT-scan) according to RECIST v1.1. Patients must have clinically and/or radiographically documented measurable disease. At least one site of disease must be unidimensionally measurable as follows

   • CT-scan, physical exam ≥ 10 mm
   • Lymph node short axis ≥ 15 mm Tumor measurements must be performed within 28 days prior to starting study drug

8. Women of childbearing potential and men must agree to use adequate contraception when sexually active. This applies since signing of the informed consent form and up to 12 months (for women of child bearing potential) and 6 months (for fertile men) after the last study drug administration (Copanlisib). Highly effective contraception methods are detailed in section 7.2

9. Women of childbearing age or sexually active female patients with reproductive potential must have a negative pregnancy test (serum or urine within the 7 days prior to starting study drug)

10. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses

11. Patients with social insurance coverage

12. Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m² according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula (within 7 days prior to starting study drug). If not on target, this evaluation may be repeated once after at least 24 hours either according to the MDRD abbreviated formula or by 24 hour sampling. If the later result is within acceptable range, it may be used to fulfill the inclusion criteria instead

Exclusion Criteria:

1. Patients previously treated with PI3K and/or mTOR inhibitors

2. Patients with anticancer therapy (radiotherapy, immunotherapy, chemotherapy, etc.) within 28 days or investigational treatment within 28 days prior to the initiation of study drug treatment, unless evidence of progression since last treatment

3. Patients currently using other approved or investigational anti-neoplasic agent

4. Patients with uncontrolled arterial hypertension despite optimal medical management, Congestive heart failure > New York Heart Association (NYHA) class 2, Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of test drug No active cardiac disease including any of the following: left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Gated Acquisition (MUGA) scan or echocardiogram (ECHO) and QTc > 470 ms on screening ECG

5. Patients with uncontrolled diabetes mellitus (patients with controlled Type I or II diabetes mellitus will be eligible but only into the phase II of the study and only if fasting HbA1c ≤ 8.5% at screening)

6. Patients with a history of Human Immunodeficiency Virus (HIV) Hepatitis B (HBV) or hepatitis C (HCV) infection. All patients must be screened for HIV, HBV and HCV up to 28 days prior to first dosing using the routine virus laboratorial panel. Patients who are positive for HBs Ag or HBc Ab will be eligible if they are negative for HBV-DNA. Patients who are positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA

7. Patients with active uncontrolled or symptomatic central nervous system (CNS) metastases. Patients are eligible if their disease is controlled at least 30 days on corticosteroids prior to starting study drug

8. Patients with major surgery within 28 days, or open biopsy within 7 days, prior to starting study drug. Patients must have recovered from major side effects of the surgery

9. Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible. Copanlisib is primarily metabolized by CYP3A4. Therefore concomitant use of strong inhibitors of CyP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and inducers of CYP3A (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, st. John's Wort) are not permitted from Day -14 of Cycle 1 until the Safety follow up visit

10. Patients with altered hematopoietic or organ function, as indicated by the following criteria (assessed within 7 days prior the first dosing):

    • Absolute granulocytes < 1.0 x 10⁹/L
    • Platelets < 75 x 10⁹/L
    • ALAT/ASAT > 2.5 x ULN in the absence of or > 5 x ULN in the presence of liver metastases
    • Bilirubin > 1.5 x ULN (except Gilbert Syndrome: < 3.0 mg/dL)
    • Creatinine clearance < 60 mL/min (measured or calculated by Cockcroft and Gault formula) or serum creatinine > 1.0 x ULN
    • Lipase > 1.5 x ULN
    • INR and PTT > 1.5 x ULN

11. Patients with a history of hypersensitivity to other monoclonal antibodies or to the active or inactive excipients of study drug

12. Known drug or alcohol abuse

13. Known or underlying medical condition that, in the investigator's opinion, would make the administration of study drug hazardous to the patient or obscure the interpretation of toxicity determination or adverse events

14. History of uncontrolled seizures, seizure disorder requiring medication, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake

15. Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study

16. Individuals deprived of liberty or placed under the authority of a tutor

17. Previous or concurrent history of malignancies within 5 years prior to study treatment except for curatively treated:

    • Cervical carcinoma in situ
    • Non-melanoma skin cancer
    • Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])
    • Localized prostate cancer

18. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication

19. Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or estimated by urine protein-creatinine ratio > 3.5 on a random urine sample

20. History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)

21. Concurrent diagnosis of pheochromocytoma

22. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment

23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia

24. Ongoing immunosuppressive therapy

25. Blood or platelets transfusion less than 7 days before starting treatment

26. Myeloid growth factors within 14 days prior to treatment

27. Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not allowed. Previous corticosteroid therapy must be stopped or reduced to the allowed dose 7 days before performing the screening CT scan/MRI, whichever is performed first, and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose after the patient has signed the IC. Patients may be using topical or inhaled corticosteroids

28. History of having received an allogeneic bone marrow or organ transplant

29. Anti-arrhythmic therapy (beta blockers or digoxin are permitted)

Individual Participant Data will not be shared at an individual level. Those data will be part of the study database including all enrolled patients.