Clinical Trials /

Atezolizumab in Combination With Chemotherapy for Pediatric Relapsed/Refractory Solid Tumors

NCT04796012

Description:

This trial is a multi-center, non-randomized, open-label Phase II study evaluating the feasibility and efficacy of vincristine, irinotecan, temozolomide, and atezolizumab. The trial will enroll patients with pediatric relapsed/refractory solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab in Combination With Chemotherapy for Pediatric Relapsed/Refractory Solid Tumors
  • Official Title: Atezolizumab in Combination With Chemotherapy for Pediatric Relapsed/Refractory Solid Tumors: An Open-label, Phase II, Single-arm, Multi-center Trial

Clinical Trial IDs

  • ORG STUDY ID: SOL0620KC
  • NCT ID: NCT04796012

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab with vincristine, irinotecan and temozolomide
VincristineAtezolizumab with vincristine, irinotecan and temozolomide
IrinotecanAtezolizumab with vincristine, irinotecan and temozolomide
TemozolomideAtezolizumab with vincristine, irinotecan and temozolomide

Purpose

This trial is a multi-center, non-randomized, open-label Phase II study evaluating the feasibility and efficacy of vincristine, irinotecan, temozolomide, and atezolizumab. The trial will enroll patients with pediatric relapsed/refractory solid tumors.

Detailed Description

      In this study, we will test the combination of atezolizumab with chemotherapy for relapsed
      solid tumors in childhood. This combination has not been tested. Thus, in the first cohort,
      investigators will determine the feasibility of administering vincristine, irinotecan,
      temozolomide, and atezolizumab simultaneously in children with relapsed or refractory solid
      tumors, regardless of PD-L1 status. In the next cohort, investigators will determine the
      objective response rate (ORR), duration of response, and progression-free survival of
      children with PD-L1(+) relapsed or refractory solid tumors treated with vincristine,
      irinotecan, temozolomide, and atezolizumab.
    

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab with vincristine, irinotecan and temozolomideExperimentalAtezolizumab will be administered by intravenous (IV) infusion at a dose of 15 mg/kg (maximum 1200 mg) on Day 1 of each 21-day cycle, along with vincristine, irinotecan, and temozolomide at the above doses. Treatment will continue for up to 2 years or until the participant experiences disease progression or an unacceptable toxicity.
  • Atezolizumab
  • Vincristine
  • Irinotecan
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent

          2. Relapsed or refractory solid tumor after at least one prior course of therapy. Hodgkin
             lymphoma or non-Hodgkin lymphoma are not permitted. Patients with CNS malignancy or
             asymptomatic CNS metastases may be enrolled, provided all of the following criteria
             are met. No metastatic or primary disease affecting the brainstem, midbrain, pons, or
             cerebellum, or within 10 mm of optic nerve. No history of leptomeningeal disease No
             history of intracranial or spinal cord hemorrhage. No evidence of progression of
             neurologic deficit, in the investigator's judgment, within 7 days prior to initiation
             of study medications.

          3. Age ≥ 6 months and ≤ 30 years

          4. Lansky Performance Status (patients < 16 years old) or Karnofsky Performance Status
             (patients ≥ 16 years old) ≥ 50

          5. Ability to comply with the study protocol, in the investigator's judgment

          6. For efficacy cohort, disease must be measurable as defined by RECIST v1.1, mINRC, or
             RANO criteria (as appropriate). For the feasibility cohort, disease must be evaluable,
             but patients enrolled on the feasibility cohort will be prospectively assessed for
             measurable disease. If they are deemed to have measurable disease and PD-L1(+)
             staining, they will also be included in the efficacy cohort. Previously irradiated
             lesions can be considered as measurable disease only if progressive disease has been
             unequivocally documented at that site since radiation.

          7. For the efficacy cohort, PD-L1(+) tumor is required. Staining may be performed in the
             central site CAP/CLIA -certified laboratory using the 22c3 antibody for
             immunohistochemical analysis. PD-L1(+) status will be defined as staining on ≥1% of
             tumor cells or ≥1% of stroma. For the feasibility cohort, PD-L1 positivity is not
             required but will be performed centrally in all cases for exploratory biomarker
             studies.

          8. Availability of a tumor specimen suitable for determination of PD-L1 status, either
             from initial diagnosis or from a recurrence. For PD-L1 staining to be performed at the
             central site, a formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin
             block (preferred) or at least 15 slides containing unstained, freshly cut, serial
             sections must be available along with an associated pathology report prior to study
             enrollment. Patients for whom the required number of slides are not available may
             still be eligible to enroll on study with PI approval

          9. Adequate organ and marrow function as defined by the following laboratory values
             obtained within 21 days prior to initiation of study medication.

               1. For patients without known bone marrow involvement: (1) Absolute neutrophil count
                  ≥ 1.0 x 10^9 / L (1000/µL) without granulocyte colony-stimulating factor support
                  (≥14 days after the last dose of a long-acting growth factor such as
                  pegfilgrastim, or 7 days after short-acting growth factor), (2) Absolute
                  lymphocyte count ≥ 0.5 x 10^9 / L (500/µL), (3) Platelet count ≥ 75 x 10^9 / L
                  (75,000/µL) without transfusion in the last 7 days.

               2. Patients with known bone marrow metastatic disease will be eligible for the study
                  if they meet the following criteria: (1) Absolute neutrophil count (ANC) ≥
                  750/mm3, (2) Absolute lymphocyte count ≥ 0.4 x 10^9 / L (400/µL), (3) Platelet
                  count ≥ 50,000/mm3 (may receive transfusions provided they are not known to be
                  refractory to red cell or platelet transfusions).

               3. Total bilirubin ≤1.5 x upper limit of normal (ULN) for age

               4. AST (SGOT) and ALT (SPGT) ≤ 2.5 x ULN for age

               5. Creatinine ≤ 1.5 x ULN for age or creatinine clearance (or radioisotope
                  glomerular filtration rate) ≥ 70 mL/min/1.73 m2 f Left ventricular ejection
                  fraction ≥ 50% or shortening fraction ≥ 30%

         10. Negative HIV and hepatitis B surface antigen (HBsAg) tests at screening

         11. For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive methods, and agreement to refrain from
             donating eggs, as defined below:

               1. Women must remain abstinent or use contraceptive methods with a failure rate of
                  less than 1% per year during the treatment period and for 5 months after the
                  final doses of atezolizumab, vincristine, and temozolomide. Women must refrain
                  from donating eggs during this same period.

               2. A woman is considered to be of childbearing potential if she is postmenarchal,
                  has not reached a postmenopausal state (12 or more continuous months of
                  amenorrhea with no identified cause other than menopause), and has not undergone
                  surgical sterilization (removal of ovaries and/or uterus), regardless of sexual
                  orientation or marital status.

         12. For men who are not surgically sterile: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive measures, and agreement to refrain from
             donating sperm, as defined below:

               1. With a female partner of childbearing potential who is not pregnant, men must
                  remain abstinent or use a condom plus an additional contraceptive method that
                  together result in a failure rate of less 1% per year during the treatment period
                  and for 5 months after the final doses of atezolizumab, irinotecan, and
                  temozolomide. Men must refrain from donating sperm during this same period.

               2. The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical trial and the preferred and usual lifestyle of the
                  patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
                  postovulation methods) and withdrawal are not adequate methods of contraception

        Exclusion Criteria:

          1. Pregnancy or breastfeeding or intention of becoming pregnant during study treatment or
             within 5 months after the final dose of study treatment. Women of childbearing
             potential must have a negative serum pregnancy test result within 21 days prior to
             initiation of study treatment.

          2. Medical conditions that are excluded:

               1. Active or history of autoimmune disease or immune deficiency, including, but not
                  limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
                  erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
                  antibody syndrome, Guillain-Barré syndrome, multiple sclerosis, or Kawasaki
                  syndrome with the following exceptions:

                    -  Patients with a history of autoimmune-related hypothyroidism who are on
                       thyroid-replacement hormone are eligible for the study.

                    -  Patients with controlled Type 1 diabetes mellitus who are on an insulin
                       regimen are eligible for the study.

                    -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                       dermatologic manifestations only (e.g., patients with psoriatic arthritis
                       are excluded) are eligible for the study provided all of following
                       conditions are met at study initiation: (1) Rash must cover less 10% of body
                       surface area, (2) Disease is well controlled at baseline and requires only
                       low-potency topical corticosteroids, (3) No occurrence of acute
                       exacerbations of the underlying condition requiring psoralen plus
                       ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
                       calcineurin inhibitors, or high-potency or oral corticosteroids within the
                       previous 12 months

               2. Uncontrolled or symptomatic hypercalcemia (ionized calcium less than 1.5 mmol/L,
                  calcium less than 12 mg/dL or corrected serum calcium less than ULN)

               3. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring
                  recurrent drainage procedures (once monthly or more frequently). Patients with
                  indwelling catheters (e.g., PleurX) are allowed.

               4. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a
                  stable regimen at study entry for at least 2 weeks. Intermittent use of as needed
                  medication is allowed during this period.

               5. Clinically significant gastrointestinal disorder that may interfere with
                  absorption of orally administered drugs (at the discretion of the treating
                  physician)

               6. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
                  bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis,
                  or evidence of active pneumonitis on screening chest computed tomography (CT)
                  scan. History of radiation pneumonitis in the radiation field (fibrosis) is
                  permitted.

               7. Significant cardiovascular disease (such as New York Heart Association Class II
                  or greater cardiac disease, myocardial infarction, or cerebrovascular accident)
                  within 3 months prior to initiation of study treatment, unstable arrhythmia, or
                  unstable angina

               8. History of severe asthma or uncontrolled asthma i Dyspnea at rest or requirement
                  for supplemental oxygen

             j. Uncontrolled seizures. Patients taking a stable dose of anticonvulsants (for 2
             weeks) are permitted, as long as they are not strong inducers or inhibitors of CYP3A4.

             k. Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding that contraindicates the use of an investigational drug, may affect
             the interpretation of the results, or may render the patient at high risk from
             treatment complications in the opinion of the treating investigator

          3. Washout periods from prior therapies:

               1. Myelosuppressive chemotherapy or radiotherapy within 21 days prior to starting
                  study treatment. Subjects must have recovered from all acute prior
                  treatment-related toxicities to grade 1 or baseline (excluding alopecia and
                  clinically stable toxicities requiring ongoing medical management, such as
                  hypothyroidism).

               2. Non-myelosuppressive cancer therapy, such as kinase inhibitors, within 7 days
                  prior to study treatment.

               3. Treatment with monoclonal antibodies with long half-lives, within 3 half-lives
                  prior to study treatment.

               4. Treatment with targeted cellular therapies within 28 days prior to starting study
                  treatment.

               5. Major surgical procedure, other than for diagnosis, within 30 days prior to
                  initiation of study treatment, or anticipation of need for a major surgical
                  procedure during the first four cycles of the study.

                    -  Biopsy tissue collection or placement of a vascular access device is
                       permitted if the site has healed prior to initiation of study medications.

                    -  For patients with CNS disease, no neurosurgical resection, brain biopsy, or
                       stereotactic/whole-brain radiation within 30 days prior to Cycle 1, Day 1

               6. Treatment with a live, attenuated vaccine within 30 days prior to initiation of
                  study treatment, or anticipation of need for such a vaccine during atezolizumab
                  treatment or within 5 months after the final dose of atezolizumab

               7. Treatment with investigational therapy within 21 days prior to initiation of
                  study treatment or concurrent participation with another investigational agent

               8. Treatment with systemic immunostimulatory agents (including, but not limited to,
                  interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug
                  (whichever is longer) prior to initiation of study treatment

               9. Treatment with systemic immunosuppressive medication (including, but not limited
                  to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide,
                  and anti-TNF-agents) within 2 weeks prior to initiation of study treatment, or
                  anticipation of need for systemic immunosuppressive medication during study
                  treatment, with the following exceptions:

                    -  Patients who received acute, low-dose systemic immunosuppressant medication
                       or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48
                       hours of corticosteroids for a contrast allergy) are eligible for the study
                       after Principal Investigator confirmation has been obtained.

                    -  Patients who received mineralocorticoids (e.g., fludrocortisone),
                       corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma,
                       or low-dose corticosteroids for orthostatic hypotension or adrenal
                       insufficiency are eligible for the study.

                    -  Patients with CNS disease can be receiving concurrent treatment with
                       corticosteroids with approval from the Principal Investigator. Patients must
                       be receiving a stable or decreasing dose for ≥ 5 days prior to the baseline
                       MRI scan and at the time of drug initiation. The Principal Investigator
                       should be informed when steroid doses are increased because of declining
                       patient status.

              10. Use of strong CYP3A4 inhibitors or inducers or strong UGT1A1 inhibitors within 12
                  days of Cycle 1, Day 1.

              11. Treatment with high-dose chemotherapy and hematopoietic stem-cell rescue within 3
                  months prior to initiation of study drug

              12. Treatment with herbal cancer therapy within 1 week prior to initiation of study
                  medications.

              13. Treatment with a long-acting hematopoietic growth factor (such as pegfilgrastim)
                  within 2 weeks prior to initiation of study medications, or a short-acting
                  hematopoietic growth factor (such as G-CSF) within 1 week prior to initiation of
                  study medications.

          4. Prior treatments:

               1. Prior allogeneic stem cell or solid organ transplantation

               2. Prior treatment with CD137 agonists or immune checkpoint blockade therapies to
                  include all anti-PD-1, and anti-PD-L1 therapeutic antibodies

               3. Subjects must not have previously progressed while receiving regimens that
                  include irinotecan or temozolomide. Patients who have received irinotecan or
                  temozolomide and did not progress while on these medications are eligible.

          5. Known ongoing or untreated infection, including, but not limited to bacteremia, active
             tuberculosis, severe pneumonia, current treatment with anti-viral therapy for HBV,
             active hepatitis C

             a. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract
             infection or chronic obstructive pulmonary disease exacerbation) are eligible for the
             study.

          6. Known allergy or hypersensitivity to any component of the study medications

               1. History of severe allergic anaphylactic reactions to chimeric or humanized
                  antibodies or fusion proteins

               2. Known hypersensitivity to Chinese hamster ovary cell products or to any component
                  of the atezolizumab formulation
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:6 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with Dose-limiting Toxicities (DLTs)
Time Frame:Beginning of cycle 3, or 30 days after the second cycle has started, whichever is earlier (each cycle is 21 days)
Safety Issue:
Description:DLT is defined as any event that is possibly, probably, or definitely attributable to the treatment regimen and exceeds the protocol defined threshold for severity

Secondary Outcome Measures

Measure:Duration of response
Time Frame:Up to 18 weeks post treatment
Safety Issue:
Description:Measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started)
Measure:Duration of response
Time Frame:Week 18 up to 24 months post treatment
Safety Issue:
Description:Measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started)
Measure:Duration of response
Time Frame:Month 24 up to end of study (approximately 48 months)
Safety Issue:
Description:Measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started)
Measure:Progression-free survival (PFS)
Time Frame:Up to 18 weeks post treatment
Safety Issue:
Description:PFS is defined as the interval between the first day of treatment and the date of disease progression or death due to any cause, whichever occurred first (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Measure:Progression-free survival (PFS)
Time Frame:Week 18 up to 24 months post treatment
Safety Issue:
Description:PFS is defined as the interval between the first day of treatment and the date of disease progression or death due to any cause, whichever occurred first (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Measure:Progression-free survival (PFS)
Time Frame:Month 24 up to end of study (approximately 48 months)
Safety Issue:
Description:PFS is defined as the interval between the first day of treatment and the date of disease progression or death due to any cause, whichever occurred first (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Measure:Overall survival (OS)
Time Frame:Up to 18 weeks post treatment
Safety Issue:
Description:OS will be characterized as both the percentage of participants without event (death) as well as median time to event (death)
Measure:Overall survival (OS)
Time Frame:Week 18 up to 24 months post treatment
Safety Issue:
Description:OS will be characterized as both the percentage of participants without event (death) as well as median time to event (death)
Measure:Overall survival (OS)
Time Frame:Month 24 up to end of study (approximately 48 months)
Safety Issue:
Description:OS will be characterized as both the percentage of participants without event (death) as well as median time to event (death)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Matthew Campbell

Trial Keywords

  • relapsed solid tumor
  • refractory solid tumor

Last Updated

March 12, 2021