Background
Methods and analysis
Study objectives
- To evaluate OS,
- To evaluate PFS,
- To evaluate health-related quality of life (HRQoL),
- To evaluate ORR,
- To evaluate the tolerance of DCF in in association with atezolizumab,
- To evaluate the predictive value of HPV-specific and telomerase-specific T cell responses monitored before and after treatment,
- To analyse HPV, p53, and neo-antigens genotypes and their correlation with the treatment efficacy,
- To investigate the impact of peripheral immune system status (Treg, CD4+ polarization, myeloid-derived suppressor cells [MDSC], T-cell exhaustion) on clinical outcomes and HPV/telomerase specific immunity,
- To investigate the prognostic value of tumour-infiltrating lymphocytes and PD-L1 expression,
- To explore the correlation of both peripheral CD4+ anti-telomerase immunity and PDL1 immunohistochemistry with PFS,
- To characterize the predictive value of soluble biomarkers (e.g. soluble PD-L1) and plasmatic HPV DNA monitoring,
- To evaluate the correlation between neo-antigen burden and survival at 12 months.
Patient selection
- Stage IV disease with distant metastases, or
- Locally advanced recurrence after CRT, non-eligible for salvage surgery due to the extension of the disease.
Inclusion criteria ➢ Histologically proved, metastatic or unresectable locally advanced recurrent SCCA, ➢ Age ≥ 18 years, ➢ ECOG-PS of 0 or 1, ➢ Signed written informed consent. Exclusion Criteria Non-eligibility to clinical trials: ➢ Previous received chemotherapy for metastatic disease, ➢ Previous received cisplatin, except for concomitant CRT, ➢ Previous chemotherapy taxanes or another spindle poison, ➢ Previous received anti-tumour immunotherapy (HPV vaccination is allowed), ➢ Previous radiotherapy within 28 days of randomization (14 days if radiotherapy of bone metastases), ➢ Diagnosis of additional malignancy within 3 years prior to randomization with the exception for curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer, ➢ Any medical or psychiatric condition of disease, which would make the patients inappropriate for entry into this study, ➢ Current participation in a study of an investigational agent or in the period of exclusion, ➢ Pregnancy, breast-feeding, or absence/refusal of adequate contraception for fertile patients, Non-eligibility to chemotherapy: ➢ Inadequate organ functions: uncontrolled cardiac condition, known cardiac failure, unstable coronaropathy, respiratory failure, and Chronic Obstructive Pulmonary Disease (COPD), ➢ Diabetes with vascular or neurovascular complications, ➢ Pre-existent peripheral neuropathy, ➢ HIV-positive with CD4+ count under 400 cells/mm3, ➢ Active hepatitis B or C virus (HBV or HCV) infection, ➢ Active tuberculosis, ➢ Concomitant treatment with CYP3A4 inhibitor like ritonavir, indinavir, or ketoconazole, etc. (Replacement by another drug before randomization, whenever is possible, is allowed), ➢ Known hypersensitivity or contraindication to any of the study chemotherapy drugs (taxanes, cisplatin, 5-fluorouracil), ➢ Uncontrolled infection or another life-risk condition, ➢ Known hearing impairment that contraindicates cisplatin administration, ➢ Inadequate laboratory values: creatinine clearance (CrCl by Modification of Diet in Renal Disease [MDRD] formula) < 60 ml/min, neutrophil count < 1500 /mm3, platelets < 100,000/mm3, bilirubin 2.5 x upper limit of normal (ULN), aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 x ULN or 5 x ULN with liver metastasis, ➢ Patient with known dihydropyridine dehydrogenase (DPD) deficiency or history. Non-eligible to immunotherapy: ➢ Any immunosuppressive therapy (i.e. corticosteroids > 10 mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy, ➢ Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin) is allowed, ➢ Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, ➢ Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study, ➢ Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study, ➢ Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: o Rash must cover < 10% of body surface area, o Disease is well controlled at baseline and requires only low-potency topical corticosteroids, o No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months, ➢ Prior allogeneic bone marrow transplantation or prior solid organ transplantation, ➢ Known active central nervous system metastases and/or carcinomatous meningitis. Subject with previously treated brain metastases and with radiological and clinical stability are allowed, ➢ Previously received an anti-PD1, anti-PDL1, or anti-CTLA4 agent, ➢ Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of atezolizumab formulation, ➢ History of colorectal inflammatory disease, ➢ History of idiopathic or secondary pulmonary fibrosis (history of radiation pneumonitis in the radiation field fibrosis is permitted), or evidence of active pneumonitis requiring a systemic treatment with 28 days before the planned start of study therapy, ➢ Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study, ➢ Severe infection within 4 weeks prior to initiation of study treatment. |
Treatments
Atezolizumab
mDCF
Study description (Fig. 1)
Therapeutic seqssssuence
- Arm A (66 patients): 8 cycles of the mDCF regimen every 2 weeks in association with atezolizumab administrated every 2 weeks for 12 months.
- Time-frame (TF) 1: 8 cycles of mDCF + atezolizumab (4 months).
- TF 2: 16 cycles of atezolizumab alone (8 months).
- TF 3: follow-up every 3 months for 2 years
- Arm B (33 patients): 8 cycles of the mDCF regimen every 2 weeks.
- TF 1: 8 cycles of mDCF (4 months).
- TF 2: follow-up every 2 months (8 months).
- TF 3: follow-up every 3 months for 2 years.×
Evaluation, laboratory tests, and follow-up
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Computed tomography (CT-scan) will be planned at baseline and every 8 weeks until 12 months (or disease progression) from randomization (TF 1 and 2) and every 12 weeks thereafter (TF 3) in both arms,
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Positron emission tomography (PET) scan will be performed at baseline, at the end of mDCF treatment, and at 12 months after randomization (in absence of disease progression),
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Surgery and/or palliative radiotherapy of residual metastatic sites are allowed according to the Investigator’s centre practices after week 20,
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The end of treatment visit will be performed 12 months after randomization or 4 weeks after the last cycle of treatment if treatment is stopped prematurely (progression, toxicity, or decision of physician or patient),
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Follow-up every 3 months after the end of treatment visit until patient death or at least 3 years after the randomization date.
Randomization
- Age (65 < years vs ≥ 65 years),
- Synchronous (metastases at the time of diagnosis) vs metachronous (metastases after starting a treatment for a localized disease) vs locally advanced unresectable disease and no evidence of metastases.
Quality of life assessment
- At inclusion, before randomization,
- Every 2 cycles of chemotherapy in TF 1 (mDCF),
- Every 2 months in TF 2 until the end of treatment visit,
- At the end of treatment visit,
- Every 3 months during follow-up in TF 3, until patient death, or at least 3 years after the randomization date.
Biological sample collection
- Sample N°1: At inclusion visit before the first treatment.
- Sample N°2: At 2 months from randomization.
- Sample N°3: At 6 months after randomization.
- Sample N°4: At the end-point visit.
Tumour samples
Data management
Statistical considerations
Planed number of patients to include
- H0: a PFS rate at 12 months of 35% is uninteresting,
- H1: a PFS rate at 12 months of 50% is expected.
Modality of analysis
Study schedule (Fig. 1)
Baseline
- Inclusion/exclusion criteria check, informed consent collection, and HIV serology,
- Clinically relevant medical/surgical history and associated therapies data collection,
- CT-scan and positron emission tomography (PET)-scan (if PET-scan performed more than 28 days prior to the initiation of treatment, it could be validated by the Coordinator considering the accessibility to PET-scan in given centre),
- Tumour sample collection: tumour sample realized in routine will be collected,
- Clinical evaluation: weight, ECOG-PS, vital signs (pulse, blood pressure, and body temperature),
- Blood analysis: complete blood count including red blood cells, haemoglobin, haematocrit, lymphocytes, white blood cells differentials, platelets, blood electrolytes, bicarbonates, glycemia, protein, albumin, blood urea nitrogen, creatinine, creatinine clearance (CrCl) (by Modification of Diet in Renal Disease [MDRD]), calcium, magnesium, aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (G-GTP), conjugated and total bilirubin, alkaline phosphatase (ALP), thyroid stimulating hormone (TSH), lactate dehydrogenase (LDH), C-reactive protein (CRP), amylase, lipase
- HIV, HCV, and HBV serology,
- HIV viremia for HIV+ patients,
- Serologic pregnancy test for women with childbearing potential,
- Cardiac evaluation including electrocardiogram (ECG),
- Blood sample n°1: one 6 ml EDTA tube and two 4 ml EDTA tubes (for plasma isolation and freezing) and six 6 ml EDTA tubes (for peripheral blood mononuclear cell [PBMC] storage that should be sent to Besançon Biomonitoring Platform at room temperature, cf. laboratory manual),If all eligibility criteria are verified, randomization of the patient is done via the eCRF and a treatment arm is allocated to the patient.
- Clinical evaluation: weight, height, ECOG-PS, vital signs (pulse, blood pressure and body temperature),
- Blood analysis (within 72 h prior the visit): complete blood count including red blood cells, haemoglobin, haematocrit, lymphocytes, white blood cells and differentials and platelets, blood electrolytes, bicarbonates, glycemia, protein, albumin, blood urea nitrogen, creatinine, CrCl (MDRD), calcium, magnesium, AST, ALT, G-GTP, conjugated and total bilirubin, ALP, TSH, LDH, CRP, amylase, lipase,
- Serologic pregnancy test for women with childbearing potential before each treatment administration,
- HRQoL evaluation with EORTC QLQ-C30 questionnaire: every 2 cycles (cf. Flowchart),
- Adverse events report according to NCI-CTCAE guidelines v 4.03,
- Serious adverse event/Adverse events of special interest report,
- Concomitant treatment collection,Assessment to be performed every 8 weeks from randomization to the end of treatment visit:
- CT-scan every 2 months in order to determine the impact of DCF with/without atezolizumab treatment in each patient,
- HIV viremia for HIV-positive patients.Biomonitoring: Blood sample n°2, 3: to be taken respectively at 2 and 6 months from the date of randomization: one 6 ml EDTA tube and two 4 ml EDTA tubes (for plasma isolation and freezing), and six 6 ml EDTA tubes (for PBMC storage that should be sent to Besançon Biomonitoring Platform at room temperature, cf. laboratory manual).
End of trial
Monitoring and safety
- ✓ - Ensure the safety and well-being of the patients exposed to study treatment through an ongoing review of safety data,
- ✓ - Assure the highest integrity of the trial operation and performance,
- ✓ - Evaluate ongoing safety data to detect the possibility of an unfavourable early treatment risk.
- In particular the combination of atezolizumab and mDCF will be closely followed.
- IDMC’s responsibilities are:
- ✓ -To review safety data on an ongoing basis,
- ✓ - To recommend premature discontinuation if there is strong evidence that the investigational medicinal products are harming patients,
- ✓ - To make recommendations regarding modification of the study if there is strong evidence that such change would substantially contribute to the well-being of patients.