MK-3475 in Combination With Docetaxel vs Docetaxel Alone in Non-Small Cell Lung Cancer Patients
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: MK-3475; Docetaxel
Intervention description: The dosing interval of pembrolizumab can be increased in case of toxicity.; Use on both arms as standard of care.
Intervention MeSH terms: Docetaxel; Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be randomly assigned (1:1) using a random numbers table to receive either monotherapy Docetaxel for 6 cycles or Pembrolizuymab plus Docetaxel for 6 cycles, following with maintenance therapy with Pembrolizumab until disease progression or unacceptable toxicity.
Masking: None (Open Label)
Enrollment: 78.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: PDL1; monoclonal antibody

Summary:

      This is a phase II open-label randomized clinical trial of MK-3475 (Pembrolizumab) on
      previously treated 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.
    

Eligibility 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.