Clinical Trials /

Lenvatinib, Pembrolizumab, and Paclitaxel for the Treatment of Recurrent Endometrial, Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

NCT04781088

Description:

This phase II clinical trial studies the effect of lenvatinib, pembrolizumab, and paclitaxel in treating patients with endometrial, epithelial ovarian, fallopian tube, or primary peritoneal cancer that has come back (recurrent). While all 3 study drugs are FDA approved, and 2-drug combinations have been studied, the 3- drug combination has not been studied yet. The investigators believe that the addition of pembrolizumab to weekly paclitaxel and lenvatinib (or weekly paclitaxel to pembrolizumab and lenvatinib) is highly effective and safe with manageable side effects in both recurrent endometrial and platinum resistant ovarian cancer. The purpose of this trial is to study how well lenvatinib, pembrolizumab, and weekly paclitaxel work together in women who have recurrent endometrial cancer and/or recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer, and what kind of side effects patients may experience.

Related Conditions:
  • Endometrial Carcinoma
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lenvatinib, Pembrolizumab, and Paclitaxel for the Treatment of Recurrent Endometrial, Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
  • Official Title: Phase II Study With Safety Lead-In of Lenvatinib, Pembrolizumab, and Weekly Paclitaxel for Recurrent Endometrial, Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer

Clinical Trial IDs

  • ORG STUDY ID: OSU-20172
  • SECONDARY ID: NCI-2021-01256
  • NCT ID: NCT04781088

Conditions

  • Platinum-Resistant Fallopian Tube Carcinoma
  • Platinum-Resistant Ovarian Carcinoma
  • Platinum-Resistant Primary Peritoneal Carcinoma
  • Recurrent Endometrial Carcinoma
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
LenvatinibE7080, ER-203492-00, Multi-Kinase Inhibitor E7080Treatment (paclitaxel, lenvatinib, pembrolizumab)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratTreatment (paclitaxel, lenvatinib, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (paclitaxel, lenvatinib, pembrolizumab)

Purpose

This phase II clinical trial studies the effect of lenvatinib, pembrolizumab, and paclitaxel in treating patients with endometrial, epithelial ovarian, fallopian tube, or primary peritoneal cancer that has come back (recurrent). While all 3 study drugs are FDA approved, and 2-drug combinations have been studied, the 3- drug combination has not been studied yet. The investigators believe that the addition of pembrolizumab to weekly paclitaxel and lenvatinib (or weekly paclitaxel to pembrolizumab and lenvatinib) is highly effective and safe with manageable side effects in both recurrent endometrial and platinum resistant ovarian cancer. The purpose of this trial is to study how well lenvatinib, pembrolizumab, and weekly paclitaxel work together in women who have recurrent endometrial cancer and/or recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer, and what kind of side effects patients may experience.

Detailed Description

      PRIAMRY OBJECTIVE:

      I. To determine objective antitumor activity (complete and partial response) of lenvatinib,
      pembrolizumab, and weekly paclitaxel as measured by Response Evaluation Criteria in Solid
      Tumors (RECIST) criteria in recurrent endometrial and platinum resistant ovarian cancer.

      SECONDARY OBJECTIVES:

      I. To determine the safety and tolerability weekly paclitaxel, lenvatinib, and pembrolizumab
      in study patients.

      II. To measure the progression free survival in the study population. III. To measure the
      overall survival in the study population.

      EXPLORATORY OBJECTIVE:

      I. To explore the baseline tumor genetic and microenvironment parameters predictive of
      clinical benefit or resistance to the treatment combination and potential mechanisms of
      resistance.

      OUTLINE:

      Beginning cycle 1 day 1, patients receive lenvatinib PO daily, pembrolizumab IV on day 1, and
      paclitaxel IV over 1 hour on days 1, 8, and 15, on a 21 day cycle in the absence of disease
      progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (paclitaxel, lenvatinib, pembrolizumab)ExperimentalPatients receive paclitaxel IV over 1 hour on days -15 and -8 and lenvatinib PO QD on days -15 to 0. Beginning cycle 1 day 1, patients receive lenvatinib PO QD, pembrolizumab IV over 30 minutes on day 1, and paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles with pembrolizumab repeats every 3 weeks for up to 2 years, and cycles with paclitaxel and lenvatinib repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
  • Lenvatinib
  • Paclitaxel
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants who are at least 18 years of age on the day of signing informed consent
             will be enrolled in this study

          -  Women with histologically confirmed endometrial cancer, epithelial ovarian cancer,
             fallopian tube cancer or primary peritoneal cancer (all histological subtypes)

          -  Patients must have received prior treatment with a platinum containing regimen and may
             have received 1-3 prior regimens. Hormonal therapy and maintenance therapy (with
             bevacizumab or PARP inhibitor) does not count towards the number of prior treatments

          -  Patients with ovarian, fallopian tube or primary peritoneal cancer must be platinum
             resistant (progression < 6 months after completion of a platinum containing regimen)
             or not a candidate for further platinum treatment

          -  Patients with and without mismatch repair deficiency are allowed

          -  Prior PD-1/PD-L1 inhibitors are allowed as long as this was not the most recent
             regimen and treatment was not discontinued due to side effects/toxicity. Prior weekly
             paclitaxel is allowed as long as this was not the most recent regimen and treatment
             was not discontinued due to side effects/toxicity

          -  Prior targeted therapy targeting angiogenesis is allowed as long as treatment was not
             discontinued due to side effects/toxicity

          -  Have measurable disease based on RECIST 1.1. Lesions situated in a previously
             irradiated area are considered measurable if progression has been demonstrated in such
             lesions

          -  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) as defined OR

               -  A WOCBP who agrees to follow the contraceptive guidance during the treatment
                  period and for at least 4 months (corresponding to time needed to eliminate any
                  study treatment[s] MK and or any active comparator/combination) plus 30 days (a
                  menstruation cycle) after the last dose of study treatment

          -  The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial

          -  Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
             of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)
             tissue blocks are preferred to slides. Newly obtained biopsies are preferred to
             archived tissue.

               -  Note: If submitting unstained cut slides, newly cut slides should be submitted to
                  the testing laboratory within 14 days from the date slides are cut

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
             Evaluation of ECOG is to be performed within 7 days prior to the date of allocation

          -  Absolute neutrophil count (ANC) >= 1500/uL (within 10 days prior to the start of study
             treatment)

          -  Platelets >= 100 000/uL (within 10 days prior to the start of study treatment)

          -  Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 10 days prior to the start of study
             treatment)

               -  Criteria must be met without erythropoietin dependency and without packed red
                  blood cell (pRBC) transfusion within last 2 weeks

          -  Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
             clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or
             creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5
             x institutional ULN (within 10 days prior to the start of study treatment)

               -  Creatinine clearance (CrCl) should be calculated per institutional standard

          -  Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
             bilirubin levels > 1.5 x ULN (within 10 days prior to the start of study treatment)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x
             ULN (=< 5 x ULN for participants with liver metastases) (within 10 days prior to the
             start of study treatment)

          -  International normalized ratio (INR) OR prothrombin time (PT) activated partial
             thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant
             therapy as long as PT or aPTT is within therapeutic range of intended use of
             anticoagulants (within 10 days prior to the start of study treatment)

        Exclusion Criteria:

          -  A women of child birth potential (WOCBP) who has a positive urine pregnancy test
             within 72 hours prior to registration. If the urine test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required.

               -  Note: in the event that 72 hours have elapsed between the screening pregnancy
                  test and the first dose of study treatment, another pregnancy test (urine or
                  serum) must be performed and must be negative in order for subject to start
                  receiving study medication

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks or 5 half-lives whichever is shorter prior to study entry. Patients may
             not have received biologics, targeted therapy or immunotherapy for 4 weeks (6 weeks
             for nitrosoureas or mitomycin C). Hormonal therapy is not considered anti-neoplastic
             therapy.

               -  Note: Participants must have recovered from all clinically significant treatment
                  related adverse events (AEs) due to previous therapies to =< grade 1 or baseline,
                  except grade 2 alopecia or fatigue

          -  Has received prior radiotherapy within 3 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 2-week washout is permitted
             for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system
             (CNS) disease

          -  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-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment.

               -  Note: Participants who have entered the follow-up phase of an investigational
                  study may participate as long as it has been 4 weeks after the last dose of the
                  previous investigational agent

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer in situ) that have undergone potentially curative therapy are not
             excluded

          -  Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study treatment

          -  Has severe hypersensitivity (>= grade 3) to pembrolizumab, lenvatinib, or paclitaxel
             and/or any of its excipients. Note, patients with paclitaxel hypersensitivity are
             eligible if the if infusion can safely be completed with reduced infusion rates and
             premedication

          -  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 systemic treatment

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

          -  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 the patient is at risk for, or has symptoms or signs of, hepatitis

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

          -  Known human immunodeficiency virus (HIV)-positive patients on combination
             antiretroviral therapy are ineligible because of the potential for pharmacokinetic
             interactions with pembrolizumab, lenvatinib and paclitaxel. In addition, these
             patients are at increased risk of lethal infections when treated with
             marrow-suppressive therapy. Appropriate studies will be undertaken in patients
             receiving combination antiretroviral therapy when indicated

          -  Significant cardiovascular disease, including:

               -  If the patient has a known history of decreased left ventricular ejection
                  fraction (LVEF) on imaging or clinical suggestion of heart failure, an
                  echocardiography (ECHO) or multi-gated acquisition (MUGA) should be completed.
                  Symptomatic left ventricular dysfunction or baseline left ventricular ejection
                  fraction (LVEF) by multi-gated acquisition scan (MUGA) or echocardiogram (ECHO)
                  of < lower limit of institutional normal (LVEF < 50%) will exclude the patient

               -  Patients with marked baseline prolongation of QT/corrected QT (QTc) interval (QTc
                  interval > 480 msec)

               -  Uncontrolled hypertension: systolic blood pressure of > 140 mmHg or diastolic
                  blood pressure of > 90 mmHg documented on 2 consecutive measurements taken at
                  least 24 hours apart

               -  Myocardial infarction, severe angina, or unstable angina within 6 months prior to
                  administration of first dose of study drug

               -  History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
                  ventricular fibrillation)

               -  Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial
                  fibrillation that is well controlled with anti-arrhythmic medication)

               -  Coronary or peripheral artery bypass graft within 6 months of screening

               -  History of class III or IV congestive heart failure, as defined by the New York
                  Heart Association

          -  Major surgical procedure (e.g. laparotomy, bowel resection) 4 weeks prior to start of
             the study drug. Note: If participant received major surgery, they must have recovered
             adequately from the toxicity and/or complications from the intervention prior to
             starting study treatment

          -  Neuropathy grade > 1

          -  Non-healing wound, bone fracture, or skin ulcer

          -  Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other
             gastrointestinal condition with increased risk of perforation; history of abdominal
             fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior
             to administration of first dose of study drug

          -  Patients who have a history of a small or large bowel obstruction within 2 weeks of
             screening or who have and active partial small bowel obstruction or percutaneous
             endoscopic gastrostomy (PEG)-tube

          -  Serious/active infection or infection requiring parenteral antibiotics

          -  Significant arterial or venous thromboembolic disease or vascular disorders within 6
             months prior to administration of first dose of study drug, including by not limited
             to:

               -  Cerebrovascular accident (CVA) or transient ischemic attack (TIA)

               -  Peripheral ischemia > grade 2 (per Common Terminology Criteria for Adverse Events
                  [CTCAE] version 4.03)

               -  Arterial thrombotic event

               -  Patients who have a history of deep vein thrombosis or pulmonary embolus < 3
                  months prior to enrollment must be excluded. However, if patients are on
                  therapeutic anticoagulation, and the deep vein thrombosis (DVT)/pulmonary
                  embolism (PE) has been clinically stable or improved on anticoagulation for > 3
                  months, patients are eligible.

               -  Patients with a history of clotting disorders must be excluded

          -  Significant bleeding disorders within 6 months prior to administration of first dose
             of study drug, including but not limited to:

               -  Hematemesis, hematochezia, melena or other gastrointestinal bleeding > grade 2
                  (per CTCAE version 4.03)

               -  Hemoptysis or other pulmonary bleeding > grade 2 (per CTCAE version 4.03)

               -  Hematuria or other genitourinary bleeding > grade 2 (per CTCAE version 4.03)

          -  Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that
             severely affects the absorption of study drugs, major resection of the stomach or
             small bowel, or gastric bypass procedure

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

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

          -  Is pregnant or breastfeeding, or expecting to conceive within the projected duration
             of the study, starting with the screening visit through 120 days after the last dose
             of trial treatment. Pregnant women are excluded from this study because the potential
             for teratogenic or abortifacient effects. Because there is an unknown but potential
             risk for adverse events in nursing infants secondary to treatment of the mother with
             lenvatinib, breastfeeding should be discontinued if the mother is treated lenvatinib.
             These potential risks may also apply to other agents used in this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective tumor response
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. Will be reported as a percentage and will be calculated by the number of patients with a complete or partial response divided by the total number of patients. The percentage of patients with stable disease and progressive disease will be calculated in a similar fashion.

Secondary Outcome Measures

Measure:Safety and Toxicity
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:Toxicity as assessed by Common Terminology for Adverse Events version 5.0 will be evaluated descriptively using frequencies and percentages and will be reported using tables. All patients who receive treatment, regardless of eligibility, will be evaluated for toxicity. Toxicities by type and maximum grade over the course of treatment and follow up will be summarized and by date of occurrence.
Measure:Progression free survival
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:Time from first therapy to the time of cancer progression, death or lost to follow up.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Floor Backes

Trial Keywords

  • endometrial cancer
  • ovarian cancer
  • platinum resistant
  • phase 2

Last Updated

March 4, 2021