IFCT-2201 ADAPTABLE A non-comparative randomized phase II trial evaluating the combination of paclitaxel-bevacizumab ± atezolizumab in patients with advanced non-squamous NSCLC progressing after immunotherapy and chemotherapy
- Trial ID
- 2022-502103-30-00
- Protocol
- IFCT-2201
Trial statistics
Objectives
The primary objective of this study is to evaluate the **efficacy** of the combination therapy of atezolizumab, bevacizumab, and paclitaxel compared to bevacizumab and paclitaxel alone in patients with advanced non-squamous non-small cell lung cancer (NSCLC) who have experienced progression following prior immunotherapy and chemotherapy. This evaluation is clinically relevant as it aims to determine the potential benefits of adding atezolizumab to the existing treatment regimen, which could lead to improved therapeutic outcomes for this patient population.
Secondary objectives include:
- Evaluating the efficacy of atezolizumab-bevacizumab-paclitaxel or bevacizumab-paclitaxel.
- Assessing the safety and tolerability of these treatment combinations.
- Evaluating the quality of life in patients receiving these therapies.
Participants
The clinical trial involves participants diagnosed with **advanced non-squamous non-small cell lung cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, including adequate hematologic and end-organ function, and a life expectancy of at least 12 weeks. Participants must have progressed after prior treatment with immunotherapy and platinum-based chemotherapy. The trial does not specify the total number of participants, as the sponsor has not provided this information. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The study includes a vulnerable population, and both genders are represented. Key inclusion criteria emphasize the need for measurable disease according to RECIST v1.1 and the availability of adequate tumor tissue for molecular analysis.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy involving **atezolizumab**, **bevacizumab**, and **paclitaxel** in patients with advanced non-squamous non-small cell lung cancer (NSCLC) who have progressed following prior immunotherapy and chemotherapy. This is a non-comparative, randomized, phase II trial. The study employs a double-blind, controlled methodology to ensure unbiased results. The trial is expected to run from March 2023 to May 2026, with a maximum treatment period of 60 days for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate hematologic and end-organ function, and a life expectancy of at least 12 weeks. Following the screening, participants will be randomized to receive either the combination of bevacizumab and paclitaxel with or without atezolizumab. The treatment will be administered via **intravenous infusion**. Follow-up visits will be scheduled to monitor the participants' response to the treatment, assess progression-free survival at six months, and evaluate the incidence and severity of adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.
The expected length of participant involvement is approximately 60 days, with conditions for early termination including significant adverse events or disease progression. The primary endpoint is progression-free survival at six months, as determined by an independent reviewer. Secondary endpoints include objective response rate, overall survival, and quality of life assessments. Participants must comply with scheduled visits, treatment regimens, and laboratory testing to remain in the study. The trial aims to provide valuable insights into the potential benefits of the combination therapy for patients with advanced NSCLC.
Treatment
The clinical trial involves the administration of **Bevacizumab**, a biological origin medication, formulated as a concentrate for solution for infusion. The active substance, bevacizumab, is administered via **intravenous infusion**. The dosage is calculated based on the patient's body weight, with a maximum daily and total dose of 15 mg/kg. The treatment period is set for a maximum of 60 days. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
**Paclitaxel** is another component of the trial, characterized as a chemical origin medication. It is also provided as a concentrate for solution for infusion and administered through intravenous infusion. The dosage is determined by the patient's body surface area, with a maximum daily and total dose of 200 mg/m². The treatment duration is limited to 60 days, and participant compliance is closely monitored to maintain the integrity of the study.
The trial also includes **Atezolizumab**, marketed as Tecentriq, which is a biological origin medication. It is supplied as a solution for infusion and administered intravenously. The maximum daily and total dose is 1200 mg, with a treatment period not exceeding 60 days. The administration of atezolizumab is carefully monitored to ensure participant adherence to the dosing regimen and to evaluate the efficacy of the treatment combination in patients with advanced non-squamous non-small cell lung cancer (NSCLC) progressing after prior therapies.
Efficacy
The efficacy of the treatment regimens in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)** at 6 months, as determined by an independent reviewer. Secondary endpoints include PFS at 6 months as determined by investigator assessment, Objective Response Rate (ORR), Overall Survival, and the incidence, nature, and severity of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Additionally, clinically significant changes in symptoms, function, and health-related quality of life (HRQoL) scales will be evaluated using the patient-completed European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30 LC13) and the EQ-5D-5L, including a visual analogue scale (VAS) for overall health status.
The trial will involve the administration of **atezolizumab**, **bevacizumab**, and **paclitaxel** in patients with advanced non-squamous non-small cell lung cancer (NSCLC) who have progressed after prior immunotherapy and chemotherapy. The efficacy parameters will be measured and collected at specified timepoints throughout the trial, with the primary endpoint being assessed at the 6-month mark. The analysis of these parameters will be conducted using validated scales and methodologies to ensure the accuracy and reliability of the results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal patient care. Patients must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
- Male or female aged at least 18 years old.
- ECOG Performance Status of 0 or 1.
- Histologically or cytologically documented locally advanced unresectable NSCLC (i.e. stage IIIB/IIIC not eligible for definitive chemo-radiotherapy) or metastatic NSCLC (i.e. Stage IV) (per the 8th edition of Union Internationale Contre le Cancer/American Joint Committee on Cancer [UICC/AJCC] staging system) of non-squamous histology. Note: patients with tumours of mixed histology must be classified as non-squamous or squamous based on the major histological component.
- Patients progressing after treatment with immunotherapy (anti-PD-1 or anti-PD-L1 Ab) and a doublet of platinum-based chemotherapy, given concomitantly or sequentially to the exclusion of any other treatment.
- Patients without contraindications to bevacizumab.
- The investigator must confirm prior to enrolment that the patient has adequate tumour tissue available. Tumour biopsy should be exploitable for molecular analysis. Note: Tumour tissue collected after the patient was diagnosed with metastatic disease is preferred. Tumour tissue sample must not be from previously radiated locations. Tumour sample must be one block or at least 10 unstained slides of analysable tissue. If archival tissue is either insufficient or unavailable, the patient may still be eligible upon discussion with IFCT.
- All patients must have at least one measurable target lesion according to RECIST v1.1. Previously irradiated lesions can only be considered measurable disease if disease progression has been unequivocally documented at that site since radiation and the previously irradiated lesion is not the only site of measurable disease.
- Life expectancy ≥ 12 weeks
- Adequate hematologic and end-organ function, defined by the following laboratory test results: • ANC ≥ 1500 cells/µL (without granulocyte colony-stimulating factor support within 14 days prior to C1D1). • WBC count ≥ 2500/µL. • Lymphocyte count ≥ 500/µL. • Platelet count ≥ 100 000/µL (without transfusion within 14 days prior to C1D1). • Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment as per local standard of care). • Total bilirubin ≤ 1.5 x upper limit of normal (ULN). • Patients with known Gilbert’s disease or hepatic metastasis who have serum bilirubin level ≤ 3 x ULN may be enrolled. • AST and ALT ≤ 3 x ULN, with the following exception: patients with documented liver metastases: AST and ALT ≤ 5 x ULN; ALP ≤ 2.5 x ULN; or patients with documented bone metastases: ALP ≤ 5 x ULN. • Serum albumin ≥ 2.5 g/dL. • aPTT or PTT and PT or INR ≤ 1.5 x ULN. This applies only to patients who are not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose for at least 1 week prior to C1D1.
- Measured or calculated creatinine clearance ≥ 50 mL/min calculated using the local standard method.
- Recovered from all toxicities associated with prior treatment, to acceptable baseline status, or NCI CTCAE v5.0 Grade 0 or 1, except for toxicities not considered a safety risk, such as alopecia or vitiligo. According to national (FITC) and international recommendations, certain severe immuno-induced toxicities are absolute exclusion criteria for the (re)introduction of anti-PD-L1 antibodies (atezolizumab) (e.g. pneumopathy, colitis etc.). If in doubt, please contact the IFCT.
- For women of childbearing potential (including women who have had a tubal ligation), serum pregnancy test must be performed and documented as negative within 14 days prior to C1D1.
- Women of childbearing potential must remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of study drugs. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries or uterus). Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method plus spermicide. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- Men with female partners of childbearing potential or pregnant female partners, must remain abstinent or use a condom during the treatment period and for at least 90 days after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- Participant has national health insurance coverage.
Exclusion Criteria
- Known molecular alteration of EGFR, ALK, ROS1, RET, NTRK, MET, NRG1.
- Active or history of autoimmune disease with the following exceptions: • Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study following discussion with IFCT. • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study following discussion with IFCT. • Patients with benign rheumatoid polyarthritis not needing any immunosuppressive systemic treatment. • Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g. patients with psoriatic arthritis would be excluded) are permitted provided they meet the following conditions: o Rash must cover less than 10% of body surface area (BSA). o Disease is well controlled at baseline and only requires low potency topical steroids. o No acute exacerbations of the underlying condition within the last 12 months requiring treatment with either PUVA (psoralen plus ultraviolet A radiation), methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral steroids.
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
- Patients previously treated by bevacizumab combined with first-line chemotherapy for NSCLC.
- History of idiopathic pulmonary fibrosis (including pneumonitis), organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Patients with a known history of a positive test for HIV or known AIDS who have not received effective antiretroviral therapy (ART) for the last 4 weeks and who have an HIV viral load >200 copies/mL, regardless of CD4+ T-cell count.
- Patients with known acute viral hepatitis B or C (HBV, HBC) according to serological tests. Patients with serological sequalae of cured viral hepatitis are eligible.
- Administration of live, attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation that such a live attenuated vaccine will be required during the study. Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to enrolment or at any time during the study, and for 5 months following the last study treatment.
- Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone > 10 mg/day, cyclophosphamide, azathioprine, methotrexate, thalidomide, and tumour necrosis factor [TNF-α] antagonists) within 2 weeks prior to randomization. Patients who have received acute, low dose, systemic immunosuppressant medications (e.g. a one-time dose of dexamethasone for nausea) may be eligible for this study following discussion with IFCT. The use of inhaled corticosteroids is allowed. The use of mineralocorticoids (e.g. fludrocortisone) for patients with orthostatic hypotension is allowed. Physiologic doses of corticosteroids for adrenal insufficiency may be allowed after discussion with IFCT.
- Patients with a previous treatment by taxane (docetaxel, paclitaxel). A patient with a previous treatment by peri-operative taxane or in association with radiotherapy is eligible if the treatment has been stopped for more than 6 months.
- Patients with symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases are not eligible. Note: patients with previously treated or untreated brain metastases may participate, provided they are stable (e.g. without evidence of progression by radiographic imaging for at least 28 days before the first dose of study treatment and neurologic symptoms have returned to baseline). Patients must have no evidence of new or enlarging brain metastases or CNS oedema. Patients must have discontinued use of steroids (with a dose > 10 mg prednisone equivalent daily) at least 7 days before the first dose of study treatment.
- Spinal cord compression not definitively treated with surgery or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for ≥ 2 weeks prior to screening.
- Malignancies other than NSCLC within 3 years prior to randomization, with the exception of those with a negligible risk of metastasis or death, or treated with expected curative outcome (such as adequately treated in situ cervical cancer, basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer).
- Inability to comply with study or follow-up procedures.
- Pregnant, lactating, or breastfeeding women.
- Patients previously treated for unresectable stage III NSCLC are not eligible if they progressed during or within 6 months of stopping consolidation immunotherapy. Patients previously treated by peri-operative immunotherapy for stage I, II or III NSCLC are not eligible.
- Severe infections (including active tuberculosis) within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
- Received oral or IV antibiotics (including antifungals) within 2 weeks prior to randomization. Patients receiving prophylactic antibiotics (e.g. for prevention of a urinary tract infection or chronic obstructive pulmonary disease exacerbations) are eligible.
- Major surgical procedure within 4 weeks prior to randomization, or anticipation of need for a major surgical procedure during the course of the study.
- Inability to understand the local language (French).
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or that may render the patient at high risk from treatment complications.
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
- Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of the atezolizumab formulation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Mar 2023 | 156 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BEVACIZUMAB | Other | — | INTRAVENOUS INFUSION | 15 | 60 | SUB16402MIG |
PACLITAXEL | Other | — | INTRAVENIOUS INFUSION | 200 | 60 | SUB09583MIG |
Tecentriq 1,200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1200 | 60 | PRD5434939 |