Clinical Trials /

Necitumumab and Trastuzumab in Combination With Osimertinib for the Treatment of Refractory Epidermal Growth Factor Receptor (EGFR)-Mutated Stage IV Non-small Cell Lung Cancer

NCT04285671

Description:

This phase Ib/II trial studies the side effects and best dose of trastuzumab and necitumumab together with osimertinib, and to see how well they work for the treatment of stage IV non-small cell lung cancer that is EGFR-mutated, resistant to osimertinib, and has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as trastuzumab and necitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving trastuzumab and necitumumab together with osimertinib may work better than osimertinib alone in treating patients with stage IV EGFR-mutated non-small cell lung cancer.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Necitumumab and Trastuzumab in Combination With Osimertinib for the Treatment of Refractory Epidermal Growth Factor Receptor (EGFR)-Mutated Stage IV Non-small Cell Lung Cancer
  • Official Title: UCLA L-08: A Phase Ib/II Study of Combined HER Inhibition Adding Necitumumab and Trastuzumab to Osimertinib in Patients With Refractory EGFR-Mutated Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 19-002190
  • SECONDARY ID: NCI-2020-00677
  • SECONDARY ID: 19-002190
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT04285671

Conditions

  • Metastatic Lung Non-Small Cell Carcinoma
  • Refractory Lung Non-Small Cell Carcinoma
  • Stage IV Lung Cancer American Joint Committee on Cancer (AJCC) v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
NecitumumabAnti-Epidermal Growth Factor Receptor Monoclonal Antibody IMC-11F8, IMC-11F8, PortrazzaTreatment (necitumumab, trastuzumab, osimertinib)
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoTreatment (necitumumab, trastuzumab, osimertinib)
TrastuzumabABP 980, ALT02, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody, Anti-ERB-2, Anti-erbB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, Anti-p185-HER2, c-erb-2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, Herzuma, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, Ogivri, Ontruzant, PF-05280014, rhuMAb HER2, RO0452317, SB3, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar ALT02, trastuzumab biosimilar EG12014, Trastuzumab Biosimilar HLX02, Trastuzumab Biosimilar PF-05280014, Trastuzumab Biosimilar SB3, Trastuzumab-dkst, Trastuzumab-dttb, Trastuzumab-pkrb, Trastuzumab-QYYP, TrazimeraTreatment (necitumumab, trastuzumab, osimertinib)

Purpose

This phase Ib/II trial studies the side effects and best dose of trastuzumab and necitumumab together with osimertinib, and to see how well they work for the treatment of stage IV non-small cell lung cancer that is EGFR-mutated, resistant to osimertinib, and has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as trastuzumab and necitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving trastuzumab and necitumumab together with osimertinib may work better than osimertinib alone in treating patients with stage IV EGFR-mutated non-small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the recommended phase II dose (RP2D) of osimertinib and necitumumab in
      combination with trastuzumab. (Phase Ib) II. Evaluate the efficacy of osimertinib,
      necitumumab, and trastuzumab (ONT) as measured by objective response rate (ORR), which is
      defined as complete response (CR) or partial response (PR) by Response Evaluation Criteria in
      Solid Tumors (RECIST) 1.1. (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate the efficacy of ONT as measured progression free survival (PFS), duration of
      response (DoR), and overall survival (OS).

      II. To evaluate the safety and tolerability of ONT as measured by adverse events (AEs)
      defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V 5.0).

      EXPLORATORY OBJECTIVES:

      I. To assess patient-reported outcomes on health-related quality of life and adverse events.

      II. Assess potential biomarkers associated with response from liquid biopsies and optional
      but recommended baseline tissue biopsy.

      IIa. Correlate pre-and post-treatment biopsies molecular changes with response. III.
      Correlate mutant allele fraction in circulating tumor deoxyribonucleic acid (DNA) (ctDNA) via
      liquid biopsy with response.

      OUTLINE: This is a phase Ib, dose-escalation study of osimertinib and necitumumab followed by
      a phase II study.

      Patients receive necitumumab intravenously (IV) over 60 minutes and trastuzumab IV over 30-90
      minutes on days 1 and 15. Patients also receive osimertinib orally (PO) once daily (QD) on
      days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      After the completion of study treatment, patients are followed up at 30 days, every 8 weeks
      through week 24, then every 12 weeks up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (necitumumab, trastuzumab, osimertinib)ExperimentalPatients receive necitumumab IV over 60 minutes and trastuzumab IV over 30-90 minutes on days 1 and 15. Patients also receive osimertinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Necitumumab
  • Osimertinib
  • Trastuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Willing and able to provide informed consent

          -  Cytologically or histologically confirmed non-small cell lung cancer (NSCLC), that is
             stage IV (metastatic), with an activating and sensitizing EGFR mutation (e.g., exon 20
             insertion mutations are excluded). Enrollment of patients with mutations other than
             exon 19 deletion and the L858R point mutation require literature supporting
             sensitivity to EGFR tyrosine kinase inhibitors

          -  Progressed on osimertinib. Osimertinib must have been included as the last systemic
             therapy prior to trial enrollment. This excludes patients who received osimertinib in
             combination with other EGFR-tyrosine kinase inhibitor (TKI) or anti-human epidermal
             growth factor receptor (anti-HER) therapy

          -  Measurable disease, as per RECIST 1.1

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  Able to swallow the study drugs, has no known intolerance of study drugs or
             excipients, and able to comply with study requirements

          -  Absolute neutrophil count (ANC) >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

          -  Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
             creatinine clearance >= 50 mL/min for participants with creatinine levels > 1.5 X
             institutional ULN (Glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatinine clearance [CrCl])

               -  Creatinine clearance may be calculated following institutional practices

          -  Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN.

               -  If a patient experiences elevated alanine aminotransferase (ALT) > 5 X ULN and
                  elevated total bilirubin > 2 X ULN, clinical and laboratory monitoring should be
                  initiated by the investigator. For patients entering the study with ALT > 3 X
                  ULN, monitoring should be triggered at ALT > 2 X baseline

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             ALT (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for
             participants with liver metastases.

               -  If a patient experiences elevated ALT > 5 X ULN and elevated total bilirubin > 2
                  X ULN, clinical and laboratory monitoring should be initiated by the
                  investigator. For patients entering the study with ALT > 3 X ULN, monitoring
                  should be triggered at ALT > 2 X baseline

          -  Albumin >= 2.5 g/dL.

          -  International Normalized Ratio (INR) or Prothrombin Time (PT), and activated partial
             thromboplastin Time (aPTT) =< 1.5 X ULN unless participant is receiving anticoagulant
             therapy, and then only as long as PT or PTT is within therapeutic range of intended
             use of anticoagulants

          -  Left ventricular ejection fraction >= 50% as measured by transthoracic or
             transesophageal echocardiogram within 60 days prior to receiving study treatment

          -  Female participants of childbearing potential must have a negative urine or serum
             pregnancy test. If the urine test is positive or cannot be confirmed as negative, a
             serum pregnancy test will be required. The serum pregnancy test must be negative for
             the participant to be eligible, and the participant must agree to use two
             highly-effective methods of birth control from the time of the first study drug
             treatment through 180 days after the last study drug treatment, or be of
             non-childbearing potential. Non-childbearing potential is defined as follows (by other
             than medical reasons):

               -  >= 45 years of age and has not had menses for > 2 years,

               -  Participants who have been amenorrhoeic for < 2 years without history of a
                  hysterectomy and oophorectomy must have a follicle stimulating hormone value in
                  the postmenopausal range upon screening evaluation, or

               -  Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation

          -  Male participants must use a condom when having sex with a pregnant woman and when
             having sex with a woman of childbearing potential from the time of the first
             study-drug treatment through 180 days after the last study drug treatment.
             Contraception should be considered for a non-pregnant female partner of childbearing
             potential

          -  Male and female participants must agree not to donate sperm or eggs, respectively,
             from the first study-drug treatment through 180 days after the last study drug
             treatment

          -  Female participants must agree to not breastfeed during the study or for 180 days
             after the last dose of study treatment

          -  Participants must agree to not donate blood during the study or for 90 days after the
             last dose of study treatment

        Exclusion Criteria:

          -  Concurrent enrollment in another clinical study, unless enrolled only in the follow-up
             period or an observational study

          -  Any chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment in
             the prior 3 weeks, other than osimertinib. Concurrent use of hormones for
             non-cancer-related conditions (eg, insulin for diabetes and hormone replacement
             therapy) is acceptable. Stereotactic, palliative radiation for symptomatic bone
             metastases is acceptable without a washout. Stereotactic brain radiation for
             asymptomatic brain metastases is acceptable with a 7 day washout

          -  Use of any investigational anticancer therapy received within 28 days prior to the
             first dose of study drugs

          -  Prior treatment with the combination of two or more of the following therapies which
             target EGFR/HER: osimertinib (Tagrisso), erlotinib (Tarceva), gefitinib (Iressa),
             afatinib (Gilotrif), lapatinib (Tykerb), neratinib (Nerlynx), vandetanib (Caprelsa),
             cetuximab (Erbitux), trastuzumab (Herceptin), pertuzumab (Perjeta), ado-trastuzumab
             emtansine (Kadcyla), panitumumab (Vectibix), necitumumab (Portrazza), dacomitinib
             (Vizimpro), poziotinib, or other combination deemed as "combined HER-inhibition
             therapy" by the investigator

          -  Has not recovered (recovery is defined as National Cancer Institute [NC] Common
             Terminology Criteria for Adverse Events [CTCAE v5.0] grade =< 1) from the acute
             toxicities of previous therapy, except treatment-related alopecia, sensory neuropathy,
             or laboratory abnormalities otherwise meeting the inclusion requirements stated in the
             inclusion criterion. Other grade 2 or less toxicities not constituting a safety risk
             based on the investigator's judgment are acceptable

          -  Known small cell lung cancer or small cell transformation

          -  The patient has a known allergy / history of hypersensitivity reaction to any of the
             treatment components or any other contraindication to one of the administered
             treatments

          -  History or evidence of current clinically relevant coronary artery disease >= grade
             III by the Canadian Cardiovascular Society Angina Grading Scale or uncontrolled
             congestive heart failure of current >= class III as defined by the New York Heart
             Association, or unstable cardiac arrhythmia requiring medication (atrial fibrillation
             is permitted if clinically stable)

          -  The patient has experienced myocardial infarction within 6 months prior to study
             enrollment

          -  The patient has any ongoing or active infection, including active tuberculosis or
             known infection with the human immunodeficiency virus, or active, clinically
             significant infection requiring the use of parenteral anti-microbial agents, or grade
             > 2 by NCI CTCAE (v5.0) within 14 days prior to enrollment

          -  The patient is pregnant or breastfeeding, or expecting to conceive or father children
             within the projected duration of the trial, starting with the screening visit through
             180 days after the last dose of trial treatment

          -  Progressive or symptomatic brain metastases. Brain metastases that have been radiated,
             are asymptomatic, and on a stable or decreasing dose of steroids are allowed.
             Leptomeningeal disease is excluded

          -  Serious accompanying disorder or impaired organ function, including major surgery
             within 3 weeks before randomization

          -  Requirement for IV alimentation (at the time of enrollment)

          -  History of another cancer within 2 years of study initiation, with the exception of
             fully treated cancers unlikely to affect the assessment of the study treatment safety
             or efficacy including early stage breast, prostate, non-melanomatous skin, thyroid,
             cervical, or endometrial cancer

          -  Gastrointestinal disorder affecting absorption

          -  Participants must not be considered a poor medical risk due to a serious, uncontrolled
             medical disorder, nonmalignant systemic disease, or active, uncontrolled infection.
             Examples include, but are not limited to, uncontrolled ventricular arrhythmia,
             uncontrolled major seizure disorder, unstable spinal cord compression, superior vena
             cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent

          -  Patient unwilling or unable to comply with the protocol

          -  Any condition that, in the opinion of the investigator or sponsor, would interfere
             with evaluation of the investigational product or interpretation of subject safety or
             study results

          -  History of arterial or venous thromboembolism within 3 months prior to study
             enrollment. Patients with a history of venous thromboembolism beyond 3 months prior to
             study enrollment can be enrolled if they are appropriately anticoagulated

          -  Recent (within 30 days before enrollment) or concurrent yellow fever vaccination
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Identification of the recommended phase II dose (R2PD) regimen for combination osimertinib, necitumumab, trastuzumab (ONT) therapy (Phase Ib)
Time Frame:Up to 1 year
Safety Issue:
Description:Will be defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0).

Secondary Outcome Measures

Measure:Progression free survival (PFS) (Phase II)
Time Frame:Up to 1 year
Safety Issue:
Description:PFS is defined as the time from trial initiation to cancer progression per RECIST 1.1 based on investigator assessment or death due to any cause.
Measure:Duration of response (DoR) (Phase II)
Time Frame:Up to 1 year
Safety Issue:
Description:DoR is time from documentation of tumor response to disease progression.
Measure:Overall survival (OS) (Phase II)
Time Frame:Up to 1 year
Safety Issue:
Description:OS is defined as time from randomization to death by any cause.
Measure:Time to response (TTR)
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Patient reported outcomes (PROs)
Time Frame:Up to 1 year
Safety Issue:
Description:Will be assessed using Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

February 25, 2020