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MK-3475 in Combination With Docetaxel vs Docetaxel Alone in Non-Small Cell Lung Cancer Patients

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ClinicalTrials.gov Identifier: NCT02574598
Recruitment Status : Not yet recruiting
First Posted : October 14, 2015
Last Update Posted : April 8, 2016
Sponsor:
Information provided by (Responsible Party):
Oscar Gerardo Arrieta Rodríguez MD, Instituto Nacional de Cancerologia de Mexico

Brief Summary:
This is a phase II open-label randomized clinical trial of MK-3475 (Pembrolizumab) on previously treated PDL1 positive non-small cell lung cancer (NSCLC) patients . This drug has shown to allow partial response according to the immune-related response criteria and the response evaluation criteria in solid tumors (RECIST). The main endpoint is to compare the overall response rate (ORR) of MK-3475 with docetaxel or docetaxel alone in patients with advanced NSCLC.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: MK-3475 Drug: Docetaxel Phase 2

Detailed Description:

MK-3475 (MK-3475) is an IgG4 monoclonal antibody to PD1, which received a 'breakthrough therapy' designation for advanced melanoma from the FDA in January 2013. Preliminary results from the NSCLC cohort of a phase I dose expansion trial of MK-3475 were presented at the 2013 World Conference on Lung Cancer meeting. MK-3475 was administered intravenously every three weeks, and continued until disease progression based upon immune related response criteria (irRC) or unacceptable toxicity. IrRC take into account the potential for different patterns of response that can be seen with immunotherapy. Of the 38 patients with previously treated advanced NSCLC evaluable for efficacy, 9 (24 percent) achieved at least partial response by irRC. Standard oncology criteria for response (Response Evaluation Criteria In Solid Tumors, RECIST were available for 33 of these patients, with at least a partial response in seven patients (21 percent). Median overall survival was 51 weeks. Therapy was well tolerated, with one case of pneumonitis (grade 2) and one case of pulmonary edema (grade 3) reported. Tumor PDL1 expression (assessed with a different assay than that used for the trials evaluating Nivolumab and MPDL3280A; antibody used undisclosed) was available for 33 of the patients who had irRC assessments and 29 of those with standard oncology (RECIST) assessment. Of the 9 patients with PDL1 positivity and irRC response data, 6 achieved at least partial response (67 percent); of the 7 patients with PDL1 positivity and standard oncology response data, 4 achieved response (57 percent). Of note, 1 of 24 patients with PDL1 negativity achieved response by irRC; 2 of 22 patients with PDL1 negativity had response by standard oncology criteria (RECIST).

Based upon these results, a randomized phase II trial comparing MK-3475 to standard salvage docetaxel in patients with PDL1 positive advanced NSCLC has been launched (NCT01905657), however there is no study in which the synergistic activity of Docetaxel + MK-3475 were evaluated, this could open the possibility of using this drug concurrently with Docetaxel as standard therapy in patients with progression of the disease despite a double platinum-based regimen.

Measure the expression levels of PD1/PD-L1/PD-L2 subpopulations tumor cells of patients with NSCLC who come to the clinic of the National Cancer Institute and relevant way, associating their role forecast and its potential as a biomarker, relating the PD-L1 levels with clinicopathologic characteristics of the patients studied.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Crossover, Phase II Clinical Trial of MK-3475 in Combination With Docetaxel Versus Docetaxel Alone in Patients With Non-Small Cell Lung Cancer (NSCLC) Previously Treated.
Study Start Date : June 2016
Estimated Primary Completion Date : October 2017
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Docetaxel + MK-3475

Docetaxel 75 mg/m2 every 3 weeks until progression of disease

MK-3475 (administered on day 8) 200mg every 3 until progression of disease

Drug: MK-3475
The dosing interval of pembrolizumab can be increased in case of toxicity.
Other Name: pembrolizumab

Drug: Docetaxel
Use on both arms as standard of care.
Other Name: taxotere

Active Comparator: Docetaxel
Docetaxel 75 mg/m2 every 3 weeks until progression of disease followed by MK-3475 200mg every 3 until progression of disease
Drug: MK-3475
The dosing interval of pembrolizumab can be increased in case of toxicity.
Other Name: pembrolizumab

Drug: Docetaxel
Use on both arms as standard of care.
Other Name: taxotere




Primary Outcome Measures :
  1. Overall Response rate [ Time Frame: from baseline to 2 months of treatment ]
    Proportion of patients with reduction in tumor burden of a predefined amount



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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed written informed consent

    1. Patients should be signed and dated form of written informed consent approved by the IRB / IEC 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 .
  2. Target Population

    1. Subjects with locally advanced NSCLC of squamous cell and non-squamous cell (adenocarcinoma and big cells) histological or cytologically documented , those who submit Stage IIIB / IV or recurrent disease after receiving radiation treatment or surgical resection
    2. Men and women ≥ 18 years of age.
    3. Performance status Eastern Cooperative Oncology Group ( ECOG ) ≤ 1.
    4. Subjects must have measurable disease by CT or MRI according to RECIST 1.1 criteria Radiographic Evaluation of Tumor on in the span of 28 days before randomization.
    5. The target lesions may be located on a previously irradiated field exists if documented progression of disease (radiographic) in that site. Subjects progression or recurrence of the disease must have experienced during or after prior chemotherapy regimen containing platinum in metastatic disease.

      This includes individuals who meet the following criteria:

      1. Subjects who received pemetrexed, bevacizumab or erlotinib as maintenance therapy (non-progressors double platinum-based chemotherapy) and progressed are eligible However, patients who received a wild EGFR tyrosine kinase inhibitor after failure of prior platinum-based therapy were excluded.
      2. Eligible patients who received double- platinum -based chemotherapy in adjuvant or neo adjuvant (after surgery and / or radiation) and developed recurrent or metastatic disease within 6 months after treatment ends
      3. Eligible individuals with recurrent disease > 6 months after adjuvant chemotherapy or neoadjuvant platinum-based , who also subsequently progressed during or after one platinum-based doublet regimen to treat recurrences
      4. Subjects with a known mutation of EGFR and received EGFR TKI (erlotinib , gefitinib or experimental) and double platinum-based chemotherapy ( regardless of the order of administration).
      5. subjects with known ALK translocation double receiving platinum-based chemotherapy and ALK inhibitor ( crizotinib or experimental )
      6. patients who have received >30Gy to the chest should have waited at least 6 months from completing radiation to starting pembrolizumab.
    6. must be available a blood sample, for evaluation of biomarkers. Samples must be received by the central laboratory before randomization.
    7. All baseline laboratory requirements will be evaluated , and must be obtained -14 days of randomization. The screening laboratory values must meet the following criteria:

    i) WBC ≥ 2000/μL ii) iNeutrophils ≥ 1500/μL iii) Platelets ≥ 100 x 10 ³ / uL iv) Hemoglobin ≥ 9.0 g / dL v) Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 40 mL / min (using the Cockcroft / Gault ) Women : CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg / dL Males: CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg / dL vi) ≤ 1.5 X ULN AST vii) ≤ 1.5 X ULN ALT viii) Total bilirubin ≤ 1.5x ULN (except for subjects with Gilbert 's Syndrome who must have total bilirubin < 3.0 mg / dL ) h ) pretreatment with radiotherapy or radiosurgery at least 3 weeks must be completed before randomization.

    i ) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

  3. Age and 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. Subjects must:

    1. Be willing and able to provide written informed consent/assent for the trial.
    2. Be > 18 years of age on day of signing informed consent.
    3. Have measurable disease based on RECIST 1.1.
    4. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion.
    5. Have a performance status of 0 or 1 on the ECOG Performance Scale.

6. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation.

Exclusion Criteria:

The subject must be excluded from participating in the trial if the subject:

  1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
  2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

    • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
  6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
  7. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
  8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
  9. Has an active infection requiring systemic therapy.
  10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02574598


Contacts
Contact: Oscar G Arrieta, MD, M Sc 56280400 ext 71101 ogar@unam.mx

Locations
Mexico
National Cancer Institute of Mexico Not yet recruiting
Mexico city, Distrito Federal, Mexico, 14080
Contact: Oscar G Arrieta, MD M Sc.    56 28 04 00 ext 71101    ogar@unam.mx   
Contact: Diana Flores Estrada    56 28 04 00 ext 71104    clinicacancerpulmonincan@gmail.com   
Principal Investigator: Oscar G Arrieta, Oncologist         
Sponsors and Collaborators
Instituto Nacional de Cancerologia de Mexico
Investigators
Principal Investigator: Oscar G Arrieta, MD, MSc National Institute of Cancer of Mexico

Publications:

Responsible Party: Oscar Gerardo Arrieta Rodríguez MD, Investigador en Ciencias Médicas "E", Instituto Nacional de Cancerologia de Mexico
ClinicalTrials.gov Identifier: NCT02574598     History of Changes
Other Study ID Numbers: INCAN/014/033/ICI
INCAN/014/033/ICI ( Other Identifier: National Cancer Institute of Mexico )
First Posted: October 14, 2015    Key Record Dates
Last Update Posted: April 8, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by Oscar Gerardo Arrieta Rodríguez MD, Instituto Nacional de Cancerologia de Mexico:
PDL1
monoclonal antibody

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Docetaxel
Pembrolizumab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action