Clinical Trials /

Copanlisib in Association With Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinomas Harboring a PI3KCA Mutation/Amplification and/or a PTEN Loss

NCT02822482

Description:

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib in Association With Cetuximab in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinomas Harboring a PI3KCA Mutation/Amplification and/or a PTEN Loss
  • Official Title: Phase ib/II Trial of Copanlisib, a Selective PI3K Inhibitor, in Combination With Cetuximab in Patients With Recurrent and/or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) Harboring a PI3KCA Mutation/Amplification and/or a PTEN Loss.

Clinical Trial IDs

  • ORG STUDY ID: UC-0130/1507
  • SECONDARY ID: 2015-004340-19
  • NCT ID: NCT02822482

Conditions

  • Carcinoma, Squamous Cell of Head and Neck

Interventions

DrugSynonymsArms
CopanlisibBAY 80-6946Copanlisib + Cetuximab
CetuximabErbituxCopanlisib + Cetuximab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Copanlisib + CetuximabExperimentalAll patients will be treated by Copanlisib in association with Cetuximab.
  • Copanlisib
  • Cetuximab

Eligibility Criteria

        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 ECOG performance status 0 - 2 (ECOG: Eastern Cooperative Oncology Group)

          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 1.1. 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 ×109/L

               -  Platelets < 75 x 109/L

               -  ALAT/ASAT > 2.5 x ULN in the absence of or > 5x 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase Ib (dose escalation phase): to determine the Maximal Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of Copanlisib in association with Cetuximab
Time Frame:1 month
Safety Issue:
Description:Determination of the MTD will be based on the occurence of Dose Limiting Toxicities during Cycle 1.

Secondary Outcome Measures

Measure:Efficacy of the combination
Time Frame:Through the study completion with an average of 10 months
Safety Issue:
Description:Objective Response Rate (ORR) using RECIST 1.1 criteria
Measure:Efficacy of the combination
Time Frame:Through the study completion with an average of 10 months
Safety Issue:
Description:Overall Survival (OS)
Measure:Adverse Events (NCI CTCAE v4.0)
Time Frame:Up to 15 cycles
Safety Issue:
Description:All Adverse Events (NCI CTCAE v4.0), related or not related to Copanlisib or Cetuximab, will be collected in the Case Report Form in order to picture the safety profile of the association.
Measure:Copanlisib Maximum Plasma Concentration [Cmax]
Time Frame:First Month (at Day 1 and Day 15)
Safety Issue:
Description:For patients enrolled in the phase Ib (dose escalation phase) pharmacokinetic samples (blood) will be collected at Cycle 1 Day 1 and Cycle 1 Day 15. There will be 5 samples per day: pre-infusion, end of infusion, 2 hours, 8 hours and 24 hours after the start of Copanlisib infusion.
Measure:Area Under the Curve [AUC] for Copanlisib pharmacokinetic
Time Frame:First Month (at Day 1 and Day 15)
Safety Issue:
Description:For patients enrolled in the phase Ib (dose escalation phase) pharmacokinetic samples (blood) will be collected at Cycle 1 Day 1 and Cycle 1 Day 15. There will be 5 samples per day: pre-infusion, end of infusion, 2 hours, 8 hours and 24 hours after the start of Copanlisib infusion.
Measure:Mutational profile of circulating tumoral DNA (ctDNA)
Time Frame:through the study duration: baseline, C1D1, C1D15, 8 weeks, disease progression
Safety Issue:
Description:For patients enrolled in the phase II (dose escalation phase) blood samples will be collected at baseline, C1D1, C1D15, 8 weeks, Disease progression or end of treatment whichever comes first.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNICANCER

Last Updated

March 29, 2017