Clinical trial NCT03556839: Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and Atezolizumab in Metastatic Carcinoma of the Cervix
Official title: A Randomized Phase III Trial of Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and Atezolizumab Versus Platinum Chemotherapy Plus Paclitaxel and Bevacizumab in Metastatic (Stage IVB), Persistent, or Recurrent Carcinoma of the Cervix
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Carcinoma of the Cervix, Stage IVB
Keywords: Cervix
Carcinoma
Atezolizumab
Lead sponsor: Grupo Español de Investigación en Cáncer de Ovario
Sponsor class: OTHER
Collaborators: name: ARCAGY/ GINECO GROUP
name: Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies
name: MaNGO
name: NSGO
name: Japanese Gynecologic Oncology Group
name: Gynecologic Oncology Group Foundation
name: AGO Study Group
name: Apices Soluciones S.L.
name: Hoffmann-La Roche
First posted: 2018-06-14
Enrollment: 410
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study will integrate the efficacy of combining the anti programmed death-ligand 1 (anti-PD-L1) agent atezolizumab with the current standard of care in Stage IVB , persistent or recurrent carcinoma of the cervix, namely cisplatin or carboplatin/paclitaxel/bevacizumab. It will be explored the combination of bevacizumab plus atezolizumab, with no patient selection based on PD-L1 expression, allowing an all-comer assessment of atezolizumab activity.

The study is a randomized open label phase III trial to investigate the impact of atezolizumab in combination with bevacizumab and cisplatin or carboplatin /paclitaxel chemotherapy on overall survival and will employ the intent to treat principle, and random assignment to one of the 2 arms will be balanced according to disease histology (squamous cell carcinoma vs adenocarcinoma), prior platinum therapy as a radiation sensitizer (no prior cis-Radiotherapy (RT) versus prior cis-RT) and chemotherapy backbone (cisplatin vs carboplatin).

This trial will be run in an open label design due to the following considerations: the control arm is the standard of care for women diagnosed with metastatic, persistant or recurrent cervical cancer because of its impact on overall survival and the primary endpoint of the study is overall survival (OS), so blinding is not needed to ensure a robust assessment.

Detailed description: Given that both Vascular Endothelial Growth Factor (VEGF) and PD-L1 appear important in cervical cancer pathogenesis, this study is designed to test the hypothesis that breaking of immune tolerance by PD-1/PD-L1 blockade will enhance the efficacy of anti-VEGF therapy in the treatment of patients with metastatic , persistent or recurrent cervical cancer. There are several data suggesting that atezolizumab and bevacizumab may be synergistic. Enhanced tumor angiogenesis is commonly associated with absence of tumor-infiltrating T cells in patients. There is evidence in ovarian cancer that tumor expression of VEGF is negatively correlated to the density of CD8+ TILs and this phenotype is associated with early recurrence, consistent with prior studies showing a correlation of VEGF to early recurrence and short survival. Furthermore, in ascites, high levels of VEGF correlate to low numbers of NK T-like CD3+CD56+ cells.

In addition to promoting tumor angiogenesis, there is increasing evidence that VEGF plays a role in cancer immune evasion through several different mechanisms. Indeed, emerging evidence suggests that the endothelium acts as a selective barrier, allowing certain T cell subsets, notably T regulatory (Treg) cells, to traffic more effectively into the tumor contributing to tumor immune tolerance. In addition, some experiments have shown that tumour hypoxia promotes the recruitment of regulatory T (T reg) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis.

Some immunosuppressive activities of VEGF, however, can be reversed by inhibition of VEGF signaling. Mice exposed to pathophysiologic levels of VEGF exhibited impaired dendritic cell function, which could be restored by blockade of VEGFR2.

In turn, the anti-tumor effect of angiogenesis blockade requires CD8+ T cells supporting the notion that VEGF-A do not simply promote tumor growth through angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs seem closely connected and cooperating to sustain tumour growth.

In addition, there is evidence that anti-VEGF therapy and immunotherapy act synergistically. Motz et al have suggested that the combination of anti-VEGF-A antibody and immunotherapy with adoptive T cell transfer led to a superior infiltration of tumor-reactive T cells than any single approach. Indeed, in a murine melanoma model, VEGF blockade synergized with adoptive immunotherapy, as evidenced by improved anti-tumor activity, prolonged survival, and increased trafficking of T cells into tumors. These data are reminiscent of the additive benefit observed in patients by combining recombinant interferon-alpha therapy and bevacizumab, a recombinant, humanized therapeutic antibody directed against VEGF, for the treatment of metastatic renal cell carcinoma.

More evidence has come from a clinical study of subjects with melanoma combining the checkpoint inhibitor (anti-CTLA-4) ipilimumab and bevacizumab. In 46 patients, the combined therapy yielded a 19.6% objective response rate, stable disease in 13%. All responses were durable \>6 months and median survival was 25.1 months, much prolonged compared to ipilimumab's expectation in metastatic melanoma. Activated vessel endothelium with extensive CD8+ T cell and macrophage cell infiltration was observed in post-treatment biopsies, as well as marked increases in CD4/CCR7/CD45ROm central memory cells in peripheral blood in the majority of patients.

Thus, an emerging paradigm supported by the data above is that angiogenesis and immune suppression are two facets of a linked biological program. Tumors seem to co-opt these existing mechanisms that are normally required to limit excessive inflammation and promote tissue recovery during infection or wound healing. The execution of this program sustains tumor growth and promotes immunologic tolerance. Because of the intimate relationship between angiogenesis and immunosuppression, it is thus expected that inhibiting both pathways will result in improved and more durable clinical benefit.

Eligibility criteria: Inclusion Criteria:

1. Female patients must be ≥18 years of age.
2. Signed informed consent before any study-specific procedure
3. Able (in the investigator´s judgment) to comply with the study protocol
4. GOG/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
5. Life expectancy ≥3 months
6. Histologically- or cytologically-confirmed diagnosis of metastatic (stage IVB), persistent, or recurrent cervical cancer (histologies other than squamous cell, adenocarcinoma, or adenosquamous will be excluded) not amenable for curative treatment with surgery and/or radiation therapy. The inclusion of patients with adenocarcinoma histology will be capped to 20% of the whole study population.
7. No prior systemic anti-cancer therapy for metastatic or recurrent disease.
8. Measureable disease by RECIST v1.1 criteria.
9. A tumor specimen is mandatory at study entry.
10. Adequate organ function:

    Hemoglobin ≥9 g/dL ANC ≥1.5 × 109/L Lymphocyte count ≥0.5 × 109/L Platelet count ≥100 x 109/L
11. Adequate liver function:

    Serum albumin ≥2.5 g/dL Total serum bilirubin ≤1.5 ×ULN AST and ALT ≤2.5 × upper limit normal (ULN) or ≤5 × ULN if tumor involvement (liver) is present
12. Adequate renal function:

    Patients with serum creatinine \<1.5 × ULN Urine dipstick for proteinuria \<2+.
13. Adequate coagulation:

    Blood coagulation parameters (PTT, PT/INR): PT such that international normalized ratio (INR) is ≤ 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of venous thrombosis including pulmonary thromboembolus) and a PTT \<1.5 × ULN.
14. Negative Test Results for Hepatitis:

    Negative hepatitis B surface antigen (HBsAg) test at screening Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening.The HBV DNA test will be performed only for patients who have a positive total HBcAb test.

    Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening.The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
15. Toxicities related to previous treatments must be recovered to \< grade 2 (with the exception of alopecia).
16. Female participants must be postmenopausal (≥ 12 months of non-therapy-induced amenorrhoea) or surgically sterile (absence of ovaries and/or uterus, or who received therapeutic radiation to the pelvis) or otherwise have a negative serum pregnancy test within 7 days of the first study treatment and agree to abstain from heterosexual intercourse or use single or combined contraceptive methods that result in a failure rate of \<1% per year during the whole treatment period of the study and for at least 5 months (if the last study dose contained atezolizumab) or 6 months (if the last study dose contained bevacizumab) after the last dose of study treatment.

    * Abstinence is acceptable only if it is in line with 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

Exclusion Criteria:

1. Disease that is suitable for local therapy administered with curative intent
2. Prior radiotherapy delivered using cobalt (rather than a linear accelerator)
3. Patients with Stage IVA not amendable to concurrent chemo-radiation as primary treatment will not be eligible.
4. Ongoing disease involving the bladder or rectum at screening/baseline
5. Evidence of abdominal free air
6. Bilateral hydronephrosis, unless it can be alleviated by ureteral stent(s) or percutaneous drainage
7. Patients previously treated with chemotherapy except when used concurrently with radiation therapy. Patients who have received either concurrent paclitaxel with radiation therapy or carboplatin/paclitaxel as adjuvant therapy are ineligible for the study.
8. Prior treatment with any anti-VEGF drug, including bevacizumab, CD137 agonists or immune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodies or anti-CTLA 4.
9. Patients with a concomitant malignancy other than non-melanoma skin cancer. Patients with a prior invasive malignancy (except non-melanoma skin cancer ) who have had any evidence of disease within the last 5 years or whose prior malignancy treatment contraindicates the current protocol therapy.
10. Known brain metastases or spinal cord compression. It is mandatory to perform a scan of the brain in cases of suspected brain metastases (CT or MRI) or spinal cord compression (MRI).
11. History or evidence, following a neurological examination, of central nervous system (CNS) disorders, unless properly treated with standard medical treatment,(e.g. uncontrolled epileptic seizures). History of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study.
12. Patients with serious non-healing wound, ulcer, or bone fracture.
13. Acute intestinal obstruction or sub-occlusion episode in the last 6 months.
14. Active GI bleeding or GI ulcer
15. History of Crohn's disease or inflammatory bowel disease
16. Prior bowel resection ≤6 weeks preceding first study dose
17. History of diverticulitis requiring medical intervention
18. NCI CTCAE (version 5.0) grade ≥2 enteritis
19. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1, Cycle 1.
20. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1, Cycle 1.
21. Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
22. Current or recent (within 10 days before the first dose of study drug) chronic daily treatment with aspirin (\>325 mg/day), clopidogrel (\>75 mg/day), or current or recent (within 10 days before first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes.
23. Patients with pre-existing Grade 2 or greater peripheral neuropathy.
24. History of any grade ≥3 venous thromboembolic event (VTE)
25. Patients with clinically significant cardiovascular disease.
26. Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower limit of normal.
27. Uncontrolled tumor-related pain
28. 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.
29. Uncontrolled hypercalcemia (\>1.5 mmol/L ionized calcium or calcium \>12 mg/dL or corrected serum calcium \> ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
30. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, glomerulonephritis or celiac disease.

    History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
31. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
32. Active tuberculosis
33. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
34. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
35. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
36. Known human immunodeficiency virus (HIV)
37. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study Influenza vaccination should be given during influenza season only
38. Any other diseases, 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 or that may affect the interpretation of the results or render the patient at high risk from treatment complications
39. Treatment with systemic immunostimulatory agents (including but not limited to IFNs, IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
40. Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to Cycle 1, Day 1 The use of corticosteroids is allowed as premedication for paclitaxel-based regimen. All patients should be premedicated prior to receiving chemotherapy (including with corticosteroids) according to the prescription information of paclitaxel and cisplatin/carboplatin and the institutional standard of care guidance.
41. Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study treatment.
42. Prior anti-cancer monoclonal antibody (mAb), prior chemotherapy, targeted small molecule therapy as first line treatment for the treatment of metastatic or recurrent cervical cancer.
43. Women that are breastfeeding or pregnant
44. Known hypersensitivity to bevacizumab, atezolizumab or any of theirs excipients (including Cremophor)
45. Demonstration of any other neurological or metabolic dysfunction, found upon physical examination or laboratory tests involving a reasonable suspicion of the existence of a disease or condition that contraindicates the use of an experimental drug, or that involves an increased risk to the patient of treatment-related complications
46. No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment.

Primary outcomes:
measure: Progression-free survival
timeFrame: 48 months
measure: Overall survival
timeFrame: 48 months
Secondary outcomes:
measure: Objective Response Rate
timeFrame: 48 months
measure: Duration of response
timeFrame: 48 months
measure: Incidence of Treatment-Emergent Adverse Events of combining atezolizumab to chemotherapy plus bevacizumab compared to cisplatin or carboplatin/paclitaxel (CP) plus bevacizumab.
timeFrame: 48 months
measure: First subsequent therapy
timeFrame: 48 months
measure: Progression-free survival 2
timeFrame: 48 months
measure: Patient-reported outcomes (PROs) of function and health related quality of life (HR-QOL) associated with atezolizumab + CP + bevacizumab compared to bevacizumab + CP alone, as measured by the functional and GHS/ HRQoL scales of EORTC QLQ-C30
timeFrame: 48 months
measure: Pharmacokinetics (PK) of atezolizumab
timeFrame: 36 months
measure: Pharmacokinetics (PK) of atezolizumab
timeFrame: 36 months
measure: Incidence of anti-therapeutic antibodies (ATAs)
timeFrame: 36 months
Other outcomes:
Locations:
city: Shreveport
country: United States
facility: Willis Knighton Cancer Center
state: Louisiana
city: Richmond
country: United States
facility: Massey Cancer Center
state: Virginia
city: Angers
country: France
facility: ICO Paul Papin
city: Besancon
country: France
facility: CHU Jean Minjoz
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Nantes
country: France
facility: Hôpital Privé du Confluent S.A.S.
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses-Croix Saint-Simon
city: Paris
country: France
facility: HEGP
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Plerin
country: France
facility: Centre CARIO-HPCA
city: Saint-herblain
country: France
facility: ICO Centre René Gauducheau
city: Strasbourg
country: France
facility: Hôpitaux Universitaires
city: Toulouse
country: France
facility: Institut Claudius Régaud
city: Villejuif
country: France
facility: Gustave Roussy
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Wuppertal
country: Germany
facility: Helios-Klinikum Wuppertal
city: Candiolo
country: Italy
facility: Fondazione Del Piemonte Per L'Oncologia
city: Ferrara
country: Italy
facility: Azienda Ospedaliero-Universitaria Di Ferrara
city: Lecce
country: Italy
facility: Ospedale Lecce 'Vito Fazzi'
city: Lecco
country: Italy
facility: ASST Lecco
city: Meldola FC
country: Italy
facility: Irst Irccs
city: Milano
country: Italy
facility: Irccs S. Raffaele - Milano
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Di Napoli Irccs Pascale
city: Padova
country: Italy
facility: Istituto Oncologico Veneto (IOV) IRCCS
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Ravenna
country: Italy
facility: AUSL Romagna - P.O. di Ravenna, Lugo, Faenza, Rimini e Cattolica
city: Reggio Emilia
country: Italy
facility: Azienda Usl - Irccs Di Reggio Emilia
city: Roma
country: Italy
facility: Policlinico Universitario A. Gemelli
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino, Presidio Sant'Anna
city: Torino
country: Italy
facility: Ospedale Ordine Mauriziano
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Integrata Di Udine
city: Fukuoka
country: Japan
facility: Kurume University Hospital
city: Hidaka
country: Japan
facility: Saitama medical university international medical center
city: Hokkaido
country: Japan
facility: Hokkaido Cancer Center
city: Hyōgo
country: Japan
facility: Hyogo Cancer Center
city: Koto-Ku
country: Japan
facility: Cancer Institute Hospital
city: Niigata
country: Japan
facility: Niigata University Medical & Dental Hospital
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Tokyo
country: Japan
facility: Keio University Hospital
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Hospitalet de LLobregat
country: Spain
facility: Intitut Català d' Oncolgia L' Hospitalet
state: Barcelona
city: Sabadell
country: Spain
facility: Parc Taulí
state: Barcelona
city: Donostia
country: Spain
facility: Hospital Universitario Donostia- Donostia Unibertsitate Ospitalea
state: Gipuzkoa
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Islas Baleares
city: Barcelona
country: Spain
facility: Hospital de la Vall d'Hebron
city: Barcelona
country: Spain
facility: H. Clínic Barcelona
city: Cordoba
country: Spain
facility: Hospital Reina Sofía Cordoba
city: Girona
country: Spain
facility: ICO Girona
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Murcia
country: Spain
facility: Hospital Clinico Universitario Virgen Arrixaca
city: Málaga
country: Spain
facility: Complejo Hospitalario Regional de Málaga
city: Santiago de Compostela
country: Spain
facility: Hosptial Clinico Universitario de Santiago de Compostela
city: Toledo
country: Spain
facility: Hospital Virgen de la Salud
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Quirón de Valencia
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
city: Linköping
country: Sweden
facility: Lindköping University Hospital
city: Lund
country: Sweden
facility: Skane University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
Study officials:
affiliation: Vall d´Hebron University Hospital
name: Ana Oaknin, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Grau JF, Farinas-Madrid L, Oaknin A. A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030). Int J Gynecol Cancer. 2020 Jan;30(1):139-143. doi: 10.1136/ijgc-2019-000880. Epub 2019 Oct 23.