This is a multi-center phase II clinical trial of atezolizumab in combination with bevacizumab as first line treatment for locally advanced or metastasic high-intermediate tumour mutation burden selected NSCLC patients. 102 patients will be enrolled in this trial to examine the efficacy of this combination measured by progression free survival according to response evaluation Criteria in solid tumours (RECIST) version 1.1.
Active, not recruiting
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Atezolizumab-Bevacizumab | Tecentriq-Avastin | Experimental: Atezolizumab plus Bevacizumab arm |
Chemotherapy-naïve patients high-intermediate TMB (TMB≥10 mutations/MB) and with locally
advanced or metastatic non-squamous non-small cell lung cancer patients will be selected.
Enroled patientswill receive 1200 mg of atezolizumab and 15mg/Kg of Avastin® (bevacizumab)
administered by IV infusion every 21 days (+/- 3 days).
The treatment will start within 1-5 days from enrolment. Atezolizumab may continue beyond
disease progression per RECIST v1.1 until loss of clinical benefit, unacceptable toxicity,
patient or physician decision to discontinue , or death. Bevacizumab will be administered
until progression disease, unacceptable toxicity, patient or physician decision to
discontinue or death.
For all patients, tumour response data collection will continue until disease progression,
even if the patient stops study treatment prior to disease progression.
The primary endpoint is to evaluate the efficacy of Atezolizumab in combination with
Bevacizumab as measured by Progression Free Survival according to RECIST Version 1.1.
PFS after enrolment is defined as the time from enrolment to the first occurrence of disease
progression or death from any cause, whichever occurs first.
Patient accrual is expected to be completed within 1.5 years excluding a run-in-period of 46
months. Treatment and follow-up are expected to extend the study duration to a total of 4.5
years. Patients will be followed 1.5 years after the end of treatment independently of the
cause of end of treatment. The study will end once survival follow-up has concluded.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Experimental: Atezolizumab plus Bevacizumab arm | Experimental | 1 group, Atezolizumab 1200mb + Bevacizumab 15 mg/kg (IV),every 21 days. |
|
Inclusion Criteria:
1. Male or female, aged ≥ 18 years old
2. ECOG performance status of 0 or 1.
3. Histologically or cytologically confirmed, Stage IIIB or IV non-squamous NSCLC
according to 8th version of the International Association for the Study of Lung Cancer
Staging Manual in Thoracic Oncology
4. No prior treatment for Stage IIIB or IV non-squamous NSCLC.
5. Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or
chemo-radiotherapy with curative intent for non-metastatic disease must have
experienced a treatment-free interval of at least 6 months from randomization since
the last chemotherapy, radiotherapy, or chemo-radiotherapy.
6. Patients with a treated asymptomatic CNS metastasis are eligible, provided they meet
all of the following criteria:
1. Only supratentorial and cerebellar metastases allowed (i.e., no metastases to
midbrain, pons, medulla or spinal cord).
2. No ongoing requirement for corticosteroids as therapy for CNS disease.
3. No stereotactic radiation within 7 days or whole-brain radiation within 14 days
prior to randomization.
4. No evidence of interim progression between the completion of CNS-directed therapy
and the screening radiographic study. Patients with new asymptomatic CNS
metastases detected at the screening scan must receive radiation therapy and/or
surgery for CNS metastases. Following treatment, these patients may then be
eligible without the need for an additional brain scan prior to inclusion, if all
other criteria are met.
7. Patients with high-intermediate Tumour Mutational Burden analysed by Foundation
Medicine (≥10 mutations/ MB) performed by a Foundation Medicine laboratory on
previously obtained archival tumour tissue or tissue obtained from a biopsy at
prescreening (sample must fulfil minimal sample requirements of 20% tumour cellularity
and a minimum surface of 25mm2).
8. Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions can only
be considered as 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 disease.
9. Adequate hematologic and organ function defined by the following laboratory results
obtained within 14 days prior to randomization:
Neutrophils ≥ 1500 cells/μL without granulocyte colony-stimulating factor support.
- Lymphocyte count ≥ 500/μL.
- Platelet count ≥ 100,000/μL without transfusion.
- Haemoglobin ≥ 9.0 g/dL. Patients may be transfused to meet this criterion.
- INR or aPTT ≤ 1.5 × upper limit of normal (ULN). This applies only to patients
who are not receiving therapeutic anticoagulation; patients receiving therapeutic
anticoagulation should be on a stable dose.
- AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:
Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN. Patients
with documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN.
- Serum bilirubin ≤ 1.25 × ULN. Patients with known Gilbert disease who have serum
bilirubin level ≤ 3 × ULN may be enrolled.
- Serum creatinine ≤ 1.5 × ULN or creatinine clearance of ≥45ml/min (based on the
Cockcroft Gault formula).
10. All patients are notified of the investigational nature of this study and signed a
written informed consent in accordance with institutional and national guidelines,
including the Declaration of Helsinki prior to any trial-related intervention.
11. For female patients of childbearing potential, agreement (by patient and/or partner)
to use a highly effective form(s) of contraception that results in a low failure rate
(< 1% per year) when used consistently and correctly, and to continue its use for 5
months after the last dose of Atezolizumab and/or 6 months after the last dose of
Bevacizumab, whichever is later. Such methods include: combined (oestrogen and
progestogen containing) hormonal contraception, progestogen-only hormonal
contraception associated with inhibition of ovulation together with another additional
barrier method always containing a spermicide, intrauterine device (IUD): intrauterine
hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on
the understanding that this is the only one partner during the whole study duration),
and sexual abstinence.
12. For male patients with female partners of childbearing potential, agreement (by
patient and/or partner) to use a highly effective form(s) of contraception that
results in a low failure rate [< 1% per year] when used consistently and correctly,
and to continue its use for 6 months after the last dose of Bevacizumab. Male patients
should not donate sperm during this study and for at least 6 months after the last
dose of Bevacizumab.
13. Oral contraception should always be combined with an additional contraceptive method
because of a potential interaction with the study drugs. The same rules are valid for
male patients involved in this clinical study if they have a partner of childbirth
potential. Male patients must always use a condom.
14. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or
surgically sterile must have a negative serum pregnancy test result within 14 days
prior to initiation of study drug.
Exclusion Criteria:
1. Patients with a sensitizing mutation in the epidermal growth factor receptor (EGFR)
gene.
2. Patients with an anaplastic lymphoma kinase (ALK) fusion oncogene.
3. Patients with an STK-1 Ligand alteration.
4. Patients with MDM2 amplification.
5. Patients with ROS1 translocations.
6. Active or untreated CNS metastases as determined by CT or magnetic resonance imaging
(MRI) evaluation during screening and prior radiographic assessments.
7. Spinal cord compression not definitively treated with surgery and/or radiation or
previously diagnosed and treated spinal cord compression without evidence that disease
has been clinically stable for > 2 weeks prior to randomization.
8. Leptomeningeal disease.
9. Uncontrolled tumour-related pain. Patients requiring pain medication must be on a
stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy
(e.g., bone metastases or metastases causing nerve impingement) should be treated
prior to initiation of study drug. Patients should be recovered from the effects of
radiation. There is no required minimum recovery period. Asymptomatic metastatic
lesions whose further growth would likely cause functional deficits or intractable
pain (e.g., epidural metastasis that is not currently associated with spinal cord
compression) should be considered for locoregional therapy, if appropriate, prior to
initiation of study drug.
10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently). Patients with indwelling
catheters (e.g., PleurX®) are allowed.
11. Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12
mg/dL or corrected serum calcium > ULN).
12. Malignancies other than NSCLC within 5 years prior to randomization, with the
exception of those with a negligible risk of metastasis or death (e.g., expected
5-year OS > 90%) treated with expected curative outcome (such as adequately treated
carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized
prostate cancer treated surgically with curative intent, ductal carcinoma in situ
treated surgically with curative intent).
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Efficacy of Atezolizumab in combination with Bevacizumab |
| Time Frame: | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months |
| Safety Issue: | |
| Description: | To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by Progression Free Survival according to Response Evaluation Criteria in Solid Tumours (RECIST). |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Fundación GECP |
August 10, 2021
