Clinical Trials /

Pembrolizumab And Lenvatinib In Leptomeningeal Metastases

NCT04729348

Description:

The purpose of this research is to examine if an experimental drug combination impacts the survival rate of individuals with Leptomeningeal Metastases This research study involves an experimental drug combination. The names of the study drugs involved in this study are: - Pembrolizumab - Lenvatinib

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab And Lenvatinib In Leptomeningeal Metastases
  • Official Title: Phase II Trial of Pembrolizumab and Lenvatinib for Leptomeningeal Metastases

Clinical Trial IDs

  • ORG STUDY ID: 20-533
  • NCT ID: NCT04729348

Conditions

  • Solid Tumor
  • Solid Tumor, Adult
  • Leptomeningeal Metastasis

Interventions

DrugSynonymsArms
PembrolizumabKeytruda®PEMBROLIZUMAB and LENVATINIB
LenvatinibLenvimaPEMBROLIZUMAB and LENVATINIB

Purpose

The purpose of this research is to examine if an experimental drug combination impacts the survival rate of individuals with Leptomeningeal Metastases This research study involves an experimental drug combination. The names of the study drugs involved in this study are: - Pembrolizumab - Lenvatinib

Detailed Description

      This is a single arm Phase 2 study of pembrolizumab in combination with lenvatinib in
      patients with leptomeningeal metastases from any solid tumor.

      The research study procedures include screening for eligibility and study treatment,
      including evaluations and follow up visits.

        -  The names of the study drugs involved in this study are:

        -  Pembrolizumab

        -  Lenvatinib

      The study treatment will last for up to 35 cycles (a cycle is 21 days long), or until the
      disease gets worse or unacceptable side effects. Participants will be followed for up to 90
      days after the end of the study treatment.

      It is expected that about 19 people will take part in this research study.

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug combination to learn whether the drug
      combination works in treating a specific disease. "Investigational" means that the drug
      combination is being studied.

      The U.S. Food and Drug Administration (FDA) has not approved pembrolizumab or lenvatinib for
      this specific disease but each has been approved for other uses.

      .

      .
    

Trial Arms

NameTypeDescriptionInterventions
PEMBROLIZUMAB and LENVATINIBExperimentalThe research study procedures include screening for eligibility and study treatment, including evaluations and follow up visits. PEMBROLIZUMAB daily, every 3 weeks LENVATINIB daily every 3 weeks
  • Pembrolizumab
  • Lenvatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed solid malignancy.

          -  Leptomeningeal metastases, as determined by: 1) positive CSF cytology, or 2) MRI
             suggestive of leptomeningeal metastases and atypical cytology.

          -  Age ≥18 years. Because no dosing or adverse event data are currently available on the
             use of pembrolizumab in combination with lenvatinib in participants <18 years of age,
             children are excluded from this study, but will be eligible for future pediatric
             trials.

          -  ECOG performance status ≤ 1 (Karnofsky ≥70%, see Appendix A)

          -  Participants must have normal organ and marrow function; all screening labs should be
             performed within 14 days of treatment initiation.

          -  Eligibility Criteria for Organ and Marrow Function

               -  Hematological

                    -  Absolute neutrophil count (ANC) ≥1500/μL

                    -  Platelets ≥100 000/μL

                    -  Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

               -  Renal

                  --- Creatinine ≤1.5 × ULN OR Measured or calculatedb creatinine clearance (GFR
                  can also be used in place of creatinine or CrCl) ≥30 mL/min for participant with
                  creatinine levels >1.5 × institutional ULN

               -  Hepatic

                    -  Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with
                       total bilirubin levels >1.5 × ULN

                    -  AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver
                       metastases)

               -  Coagulation

                    -  International normalized ratio (INR) OR prothrombin time (PT) Activated
                       partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is
                       receiving anticoagulant therapy as long as PT or aPTT is within therapeutic
                       range of intended use of anticoagulants

          -  Female participants of childbearing potential should have a negative urine pregnancy
             test within 72 hours prior to receiving the first dose of study medication. If the
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
             be required.

          -  A female participant is eligible to participate if she is not pregnant not
             breastfeeding, and at least one of the following conditions applies: Not a woman of
             childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive
             guidance during the treatment period and for at least 120 days after the last dose of
             study medication

          -  A male participant must agree to use a contraception as detailed in this protocol
             during the treatment period and for at least 120 days after the last dose of study
             treatment and refrain from donating sperm during this period.

          -  If participant is on a daily steroid medication, dose must be stable at ≤2 mg
             dexamethasone (or equivalent) for 7 days prior to initiation of treatment.

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  Participants who have received prior systemic anti-cancer therapy including
             investigational agents within 14 days of protocol treatment. Participants must have
             recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants
             with ≤Grade 2 neuropathy may be eligible.

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

          -  Participant must have recovered adequately from the toxicity and/or complications from
             any prior surgical procedures prior to starting therapy. Lenvatinib should be held for
             4 weeks following a major surgical procedure, 2 weeks following a minor surgical
             procedure.

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  HIV-positive participants on combination antiretroviral therapy are ineligible because
             of the potential for pharmacokinetic interactions with pembrolizumab. In addition,
             these participants are at increased risk of lethal infections when treated with marrow
             suppressive therapy. Appropriate studies will be undertaken in participants receiving
             combination antiretroviral therapy when indicated. No testing for HIV, Hepatitis B,
             and Hepatitis C is required unless mandated by local health authority.

          -  Participants who are receiving any other investigational agents.

          -  Has a diagnosis of immunodeficiency.

          -  Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
             detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required
             unless mandated by local health authority.

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has a known additional malignancy that is progressing or requires active treatment
             (except for patients receiving letrozole, anastrozole, exemestane, tamoxifen,
             fulvestrant, trastuzumab, bisphosphonates, denosumab or ovarian suppression therapy).
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs).Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of system.

          -  Requires treatment with high dose systemic corticosteroids defined as dexamethasone
             >2mg/day or bioequivalent within 7 days of initiating therapy.

          -  Has received systemic immunosuppressive treatments, aside from systemic
             corticosteroids as described in Section 3.2.15, within three months of start of study
             drug.

          -  Severe hypersensitivity (Grade 3 or higher) to pembrolizumab, lenvatinib, or any of
             their excipients.

          -  Has received prior treatment with any treatment targeting VEGF-directed angiogenesis,
             any anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or with an agent directed to another
             stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).

          -  Has a known history of active TB (Bacillus Tuberculosis).

          -  Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the
             first dose of study treatment.

          -  Bleeding or thrombotic disorders or participants at risk for severe hemorrhage. The
             degree of tumor invasion/infiltration of major blood vessels (e.g., carotid artery)
             should be considered because of the potential risk of severe hemorrhage associated
             with tumor shrinkage/necrosis following lenvatinib therapy.

          -  Participants having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine
             collection for quantitative assessment indicates that the urine protein is <1 g/24
             hours.

          -  Uncontrolled hypertension (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of
             an optimized regimen of antihypertensive medication.

          -  Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition
             that might affect the absorption of lenvatinib.

          -  Prolongation of corrected QT (QTc) interval to >480 milliseconds (ms).

          -  Serious nonhealing wound, ulcer, or bone fracture.

          -  Has had an allogenic tissue/solid organ transplant (large organ transplants, stem-cell
             transplant requiring chronic immunosuppressant therapy necessary to prevent graft
             rejection).

          -  Will need immediate local surgery or radiation for brain metastases.

          -  Unable to undergo MRI.

          -  Electrolyte abnormalities that have not been corrected.

          -  Significant cardiovascular impairment: history of congestive heart failure greater
             than New York Heart Association (NYHA) Class II, unstable angina, myocardial
             infarction or stroke within 6 months of the first dose of study drug, or cardiac
             arrhythmia requiring medical treatment at Screening.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of Participants alive at 6 months
Time Frame:6 months
Safety Issue:
Description:The proportion of patients alive at 6 months will be summarized with a 90% confidence interval estimated using the method of Atkinson and Brown (Biometrics, 1985), which allows for the two-stage design. Based on a sample of 19 patients, the confidence interval will be no wider than 33%

Secondary Outcome Measures

Measure:Proportion of Participants with Grade 3 or higher toxicities
Time Frame:first dose of study treatment up to the 30-Day Post Drug Visit up to 30 Months
Safety Issue:
Description:The proportion of patients with Grade 3 or higher toxicities will be presented with 90% exact binomial confidence intervals. The incidence of events that are new or worsening from the time of first dose of treatment will be summarized according to system organ class and/or preferred term, severity (based on Common Terminology Criteria for Adverse Events v5.0 CTCAE grade), type of adverse event, and relation to study treatment. Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and tabulated by primary system organ class, and type of adverse event
Measure:Proportion of evaluable participants with intracranial/intraspinal response
Time Frame:30 Months
Safety Issue:
Description:The proportion of evaluable patients with intracranial/intraspinal response (CR or PR by RANO) will be presented with a two-sided, 90% exact binomial confidence interval.
Measure:Proportion of evaluable participants with extracranial response
Time Frame:30 Months
Safety Issue:
Description:The proportion of evaluable patients with extracranial response (CR or PR by RECIST 1.1) will be presented with a two-sided, 90% exact binomial confidence interval. For a sample of 19 patients, the confidence interval will have maximum width of 33%
Measure:Intracranial/intraspinal Progression Free Survival (IPFS)
Time Frame:30 Months
Safety Issue:
Description:The distribution of intracranial/intraspinal PFS (IPFS) in participants will be summarized using the method of Kaplan-Meier. IPFS is defined as the time from registration to documented intracranial/intraspinal progression (RANO) or death, whichever occurs first. Patients who have neither died nor progressed at the time of analysis will be censored at the date of last adequate disease assessment.
Measure:Median Intracranial/intraspinal Progression Free Survival (IPFS)
Time Frame:30 Months
Safety Issue:
Description:Median IPFS will be presented and accompanied by 90% confidence intervals estimated using log(-log(survival)) methodology. Point estimates at 3 and 6 months will also be presented with confidence intervals. .
Measure:Extracranial Progression Free Survival (EPFS)
Time Frame:30 Months
Safety Issue:
Description:The distribution of extracranial PFS (EPFS) will be summarized using the method of Kaplan-Meier. EPFS is defined as the time from registration to documented extracranial progression (RANO) or death, whichever occurs first. Patients who have neither died nor progressed at the time of analysis will be censored at the date of last adequate disease assessment.
Measure:Median Extracranial Progression Free Survival (EPFS)
Time Frame:30 Months
Safety Issue:
Description:Median EPFS will be presented and accompanied by 90% confidence intervals estimated using log(-log(survival)) methodology. Point estimates at 3 and 6 months will also be presented with confidence intervals.
Measure:Overall Survival
Time Frame:30 Months
Safety Issue:
Description:The distribution of overall survival will be summarized using the method of Kaplan-Meier. (OS) is defined as the time from registration to death due to any cause, or censored at date last known alive
Measure:Median Overall Survival
Time Frame:30 Months
Safety Issue:
Description:median OS will be presented and accompanied by 90% confidence intervals estimated using log(-log(survival)) methodology. (OS) is defined as the time from registration to death due to any cause, or censored at date last known alive
Measure:Proportion of participants proportion of patients with leptomeningeal metastases from breast cancer alive
Time Frame:6 months
Safety Issue:
Description:The proportion of patients with leptomeningeal metastases from breast cancer alive at 6 months will be summarized with a 90% two-sided, exact binomial confidence interval. The maximum width of the confidence intervals is 0.55.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Solid Tumor
  • Solid Tumor, Adult
  • Leptomeningeal Metastasis

Last Updated

January 28, 2021