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Alectinib in Combination With Bevacizumab in ALK Positive NSCLC

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ClinicalTrials.gov Identifier: NCT03779191
Recruitment Status : Not yet recruiting
First Posted : December 18, 2018
Last Update Posted : December 21, 2018
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Oscar Gerardo Arrieta Rodríguez MD, Instituto Nacional de Cancerologia de Mexico

Brief Summary:

Lung cancer remains the most lethal malignancy in both sexes around the world. It is estimated that lung cancer caused 234,030 deaths in the United States in 2016, accounting for 28% of all cancer-related deaths. In 2012 alone, a total of 6,697 deaths from lung cancer were registered in Mexico; this number exceeds the death toll from other common solid neoplasms (i.e., stomach, prostate, breast, and liver). In addition to its high incidence, lung cancer patients face a dismal prognosis, with an overall 5-year survival ranging from 5-16%.

In the last two decades, the outlook for a subset of Non-small cell lung cancer (NSCLC) patients has shifted. Novel approaches have been able to identify that a significant number of patients present tumors with actionable mutations, opening the possibility of treatment with targeted therapies, which have increased survival outcomes in these patients. A number of specific therapies have been developed over the past decade, such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors.

Additionally, treatment options for patients with NSCLC with actionable mutations has increased in the last two decades, with several third generation inhibitors available, which have different efficacy and tolerability profiles, nonetheless, global 5-year survival rates remain below 20%, which highlights the need to explore therapeutic combinations which might derive in greater long-term survival for this patient subgroup. Although encouraging data has been reported in terms of adding Bevacizumab to EGFR-TKIs, this scheme has not been explored for patients who have ALK-rearranged NSCLC and who are candidates for ALK-inhibitors.

Currently, Alectinib has been shown to offer several advantages compared to first-generation ALK-TKIs, including a stronger ALK-inhibition, better outcomes in patients with Central Nervous System (CNS) involvement and longer duration of response. However, the addition of Bevacizumab to therapy with Alectinib in treatment naïve or previously treated NSCLC patients remains unexplored.

Based on this data and the need to continue searching for safe and effective therapeutic options, a phase II, single arm trial assessing Alectinib in combination with Bevacizumab in untreated and previously treated patients with Advanced or Metastatic Non-Squamous ALK-rearranged NSCLC has been designed.


Condition or disease Intervention/treatment Phase
ALK Gene Rearrangement Positive Non-Squamous Non-Small Cell Neoplasm of Lung Drug: Alectinib Drug: Bevacizumab Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Phase II, single arm trial assessing Alectinib in combination with Bevacizumab in untreated and previously treated patients with Advanced or Metastatic Non-Squamous ALK-rearranged NSCLC
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II, Open Label, Single Arm Trial of Alectinib in Combination With Bevacizumab in Untreated and Previously Treated Patients With Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) With Positive ALK Driver Mutation
Estimated Study Start Date : March 20, 2019
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : January 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Intervention
Patients in this intervention arm will receive the therapeutic combination of Alectinib dosed PO 600 mg bis in die (BID) with meals and Bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or other reasons specified in the protocol
Drug: Alectinib
Alectinib dosed 600 mg twice a day (BID) with meals until disease progression, unacceptable toxicity, or other reasons specified in the protocol
Other Name: Alecensa

Drug: Bevacizumab
Bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or other reasons specified in the protocol
Other Name: Avastin




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: Through study completion, an average of 18 months ]
    PFS based on response criteria according to RECIST 1.1 in untreated and previously treated patients with Advanced or metastatic ALK-rearranged Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab


Secondary Outcome Measures :
  1. Objective response rate [ Time Frame: 8 weeks ]
    To assess the ORR, based on response criteria according to RECIST 1.1, in untreated and previously treated patients with Advanced or Metastatic ALK-rearranged Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab.

  2. Brain- ORR [ Time Frame: 8 weeks ]
    To assess the brain ORR, based on response criteria according RECIST 1.1, in untreated and previously treated patients with Advanced or metastatic Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab.

  3. Overall survival [ Time Frame: Through study completion, an average of 18 months ]
    To assess the OS in untreated and previously treated patients with Advanced or metastatic Non-Squamous ALK-rearranged NSCLC who receive treatment with Alectinib plus Bevacizumab.

  4. Time to developing brain metastases [ Time Frame: Through study completion, an average of 18 months ]
    To assess the time since inclusion until developing brain metastases in untreated and previously treated patients with Advanced or metastatic Non-Squamous ALK-rearranged NSCLC who receive treatment with Alectinib plus Bevacizumab.

  5. Disease-related symptom improvement [ Time Frame: 12 weeks since treatment start ]
    To measure disease-related symptoms we will apply the Lung Cancer Symptom Scale (LCSS). The LCSS is designed as a disease-specific measure of quality of life particularly for use in clinical trials. It evaluates six major symptoms associated with lung mallignancies and their effect on overal symptomatic distress, functional activities, and global quality of life. The scale consists of two segments, one completed by the patient (9 items) and one completed by the health care professional (6 items). Scoring is assigned as follows: The patient scale consists of 9 visual analogue scales (100 mm horizontal line). Patient puts a mark on line to indicate intensity of response to the items in question (0 = lowest rating). The observer scale consists of a 5-point categorical scale (100=none; 75=mild; 50=moderate; 25=marked; 0=severe). The score is equal to the length of line marked by patient. An average of the aggregate score of all 9 items is the total score (0-100, 0= least symptom burden).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women, ≥18 years of age.
  2. Subjects with NSCLC with known ALK-rearrangement tested with FDA-approved test (IHQ or FISH).
  3. Subjects with sufficient tissue to test for ALK-rearranged using IHQ or FISH.
  4. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
  5. Karnofsky Performance Status of ≥70
  6. Subjects with histologically confirmed Stage 3B (IIIB), 4 (IV) or recurrent NSCLC (per the 8th International Association for the Study of Lung Cancer classification, non-squamous histology, with prior systemic chemotherapy (platinum-based) given as primary therapy for advanced disease. Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration of the prior regimen occurred at least 3 weeks prior to enrollment. Prior treatment with ALK inhibitors is permitted as long as the last administration occurred 3 weeks prior to enrollment.
  7. Subjects with CNS metastases are only eligible if the CNS metastases are adequately treated with radiotherapy and/or surgery and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 1 week prior to randomization.

    1. Patients receiving radiotherapy or radiosurgery with a dose exceeding 30 Gy will have 3 weeks for neurological stabilization before randomization.
    2. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  8. Measurable disease by CT as per RECIST 1.1 criteria.

    a. The target lesions may be located on a previously irradiated field exists if documented progression of disease (radiographic) in that site.

  9. At least 12 weeks of life expectancy.
  10. Signed written informed consent

    1. Patients should have a signed and dated form of written informed consent approved by the institutional committee in accordance with regulatory and institutional guidelines. This must be obtained before performing any procedure related to the protocol that are not part of the normal care of the patient.
    2. Patients must be willing and able to comply with scheduled visits, treatment program, laboratory testing including filling of questionnaires the results reported by the patient and other study requirements.
  11. Reproductive Status

    1. Women with reproductive potential (WOCBP) should use contraceptive methods based on tables found in Appendix 2. When a teratogenic drug test is used, and / or a drug for which there is not enough information to assess teratogenicity (have not been conducted preclinical studies) are required to use a highly effective method of contraception (failure rate less than 1 % per year). Individual methods of contraception should be determined in consultation with the researcher.
    2. The WOCBP must have a negative pregnancy test in serum or urine (minimum sensitivity 25 IU / L or equivalent units of HCG) 24 hours before starting the investigational product.
    3. Women should not be breastfeeding.
    4. Sexually active men WOCBP should use any method of contraception with a failure rate of less than 1% per year. The investigator should review contraceptive methods and the time period during which contraception to use. Men who are sexually active with WOCBP, follow the instructions of birth control for a period of 90 days, plus the time required for the investigational drug is subject to five half-lives

Exclusion Criteria:

  1. Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded. All subjects with non-squamous histology must have been tested locally for EGFR mutation status; use of an FDA-approved test is strongly encouraged (EGFR mutation testing may be performed during the Screening Period, Non-squamous subjects with unknown or indeterminate EGFR status may not be included).
  2. Subjects with untreated CNS metastases are excluded.
  3. Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
  4. Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as Vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  5. Treatment with other investigational drugs or other anti-cancer therapy, or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with this trial
  6. Radiographical evidence of cavitated or necrotic tumors
  7. Centrally located tumors with radiographical evidence (CT or MRI) of local invasion of major blood vessels
  8. History of clinically significant hemoptysis within the past 3 months
  9. History of major thrombotic or clinically relevant major bleeding event in the past 6 months.
  10. Known inherited predisposition to bleeding or thrombosis
  11. Medical History and Concurrent Diseases

    1. Any medical condition or serious uncontrolled or active infection with hepatitis or HIV that could be reactivated.
    2. Other concurrent malignancies requiring intervention.
    3. All toxicities attributed to a previous treatment for cancer other than alopecia or fatigue, must have resolved to Grade 1 (NCI CTCAE version 4) or baseline, prior to administration of study drug.
    4. Prior treatment with tumor vaccines or other anti-tumor immune stimulating agents.
    5. Prior treatment with Alectinib.
    6. Prior treatment with Bevacizumab
    7. Subjects with a history of interstitial lung disease.
    8. Subjects must be recovered from the effects of major surgery, traumatic injury or substantially at least 7 days before the first dose of study treatment.
  12. Physical Findings and Laboratory Tests

    1. Positive for the surface antigen of hepatitis B virus (HBV HBsAg) or hepatitis C ribonucleic acid (HCV RNA) Evidence indicating acute or chronic infection
    2. Known history of positive test for Human Immunodeficiency Virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS).
  13. Allergies and Adverse Drug Reactions to

    1. History of severe hypersensitivity to other monoclonal antibodies.
    2. Previous history of severe hypersensitivity reaction to paclitaxel.
    3. History of allergy or intolerance (unacceptable adverse event) to components of the study drug, or herbal teas that contain Polysorbate 80.
  14. Sexual and Reproductive Status

    1. WOCBP pregnant or who are nursing
    2. Women with a positive pregnancy test in recruitment or prior to administration of the study drug.
  15. Other Exclusion Criteria

    1. Any other serious medical condition or uncontrolled active infection, findings on physical examination, laboratory findings, altered mental status, or psychiatric condition that, in the investigator's opinion, would limit the ability of an individual to meet the requirements of study, significantly increase the risk to the subject, or which affects the interpretability of the study results.
    2. Prisoners or subjects who are involuntarily incarcerated.
    3. Subjects who are compulsorily admitted for treatment of a mental or physical illness (eg, infectious disease). Eligibility criteria for this study were carefully considered to ensure the safety of study subjects, and to ensure that the results of the study can be used

Publications:
Arrieta O, Guzmán-de Alba E, Alba-López LF, Acosta-Espinoza A, Alatorre-Alexander J, Alexander-Meza JF, Allende-Pérez SR, Alvarado-Aguilar S, Araujo-Navarrete ME, Argote-Greene LM, Aquino-Mendoza CA, Astorga-Ramos AM, Austudillo-de la Vega H, Avilés-Salas A, Barajas-Figueroa LJ, Barroso-Quiroga N, Blake-Cerda M, Cabrera-Galeana PA, Calderillo-Ruíz G, Campos-Parra AD, Cano-Valdez AM, Capdeville-García D, Castillo-Ortega G, Casillas-Suárez C, Castillo-González P, Corona-Cruz JF, Correa-Acevedo ME, Cortez-Ramírez SS, de la Cruz-Vargas JA, de la Garza-Salazar JG, de la Mata-Moya MD, Domínguez-Flores ME, Domínguez-Malagón HR, Domínguez-Parra LM, Domínguez-Peregrina A, Durán-Alcocer J, Enríquez-Aceves MI, Elizondo-Ríos A, Escobedo-Sánchez MD, de Villafranca PE, Flores-Cantisani A, Flores-Gutiérrez JP, Franco-Marina F, Franco-González EE, Franco-Topete RA, Fuentes-de la Peña H, Galicia-Amor S, Gallardo-Rincón D, Gamboa-Domínguez A, García-Andreu J, García-Cuéllar CM, García-Sancho-Figueroa MC, García-Torrentera R, Gerson-Cwilich R, Gómez-González A, Green-Schneeweiss L, Guillén-Núñez Mdel R, Gutiérrez-Velázquez H, Ibarra-Pérez C, Jiménez-Fuentes E, Juárez-Sánchez P, Juárez-Ramiro A, Kelly-García J, Kuri-Exsome R, Lázaro-León JM, León-Rodríguez E, Llanos-Osuna S, Llanos-Osuna S, Loyola-García U, López-González JS, López y de Antuñano FJ, Loustaunau-Andrade MA, Macedo-Pérez EO, Machado-Villarroel L, Magallanes-Maciel M, Martínez-Barrera L, Martínez-Cedillo J, Martínez-Martínez G, Medina-Esparza A, Meneses-García A, Mohar-Betancourt A, Morales Blanhir J, Morales-Gómez J, Motola-Kuba D, Nájera-Cruz MP, Núñez-Valencia Cdel C, Ocampo-Ocampo MA, Ochoa-Vázquez MD, Olivares-Torres CA, Palomar-Lever A, Patiño-Zarco M, Pérez-Padilla R, Peña-Alonso YR, Pérez-Romo AR, Aquilino Pérez M, Pinaya-Ruíz PM, Pointevin-Chacón MA, Poot-Braga JJ, Posadas-Valay R, Ramirez-Márquez M, Reyes-Martínez I, Robledo-Pascual J, Rodríguez-Cid J, Rojas-Marín CE, Romero-Bielma E, Rubio-Gutiérrez JE, Sáenz-Frías JA, Salazar-Lezama MA, Sánchez-Lara K, Sansores Martínez R, Santillán-Doherty P, Alejandro-Silva J, Téllez-Becerra JL, Toledo-Buenrostro V, Torre-Bouscoulet L, Torecillas-Torres L, Torres M, Tovar-Guzmán V, Turcott-Chaparro JG, Vázquez-Cortés JJ, Vázquez-Manríquez ME, Vilches-Cisneros N, Villegas-Elizondo JF, Zamboni MM, Zamora-Moreno J, Zinser-Sierra JW. [National consensus of diagnosis and treatment of non-small cell lung cancer]. Rev Invest Clin. 2013 Mar;65 Suppl 1:S5-84. Spanish.

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Responsible Party: Oscar Gerardo Arrieta Rodríguez MD, Coordinator of the Thoracic Oncology Unit and Laboratory of Personalized Medicine, Instituto Nacional de Cancerologia de Mexico
ClinicalTrials.gov Identifier: NCT03779191     History of Changes
Other Study ID Numbers: Alectinib plus Bevacizumab
First Posted: December 18, 2018    Key Record Dates
Last Update Posted: December 21, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Bevacizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors