Principal Investigator: Nicholas Whipple
Keywords: REGN281 Department: Pediatric Administration
IRB Number: 00109601
Specialty: Pediatric Hematology and Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Rebecca Bryan
rebecca.bryan@hsc.utah.edu
801-587-2253

Brief Summary

Study Design/Endpoints

Study endpoints are provided below. Study objectives are provided in Section 1. Evaluation criteria definitions are provided in the protocol.

Primary Endpoints

Phase 1
• To confirm the safety and anticipated recommended phase 2 dose (RP2D) of REGN2810 (cemiplimab) for children with recurrent or refractory solid or CNS tumors
• To characterize the PK of REGN2810 given in children with recurrent or refractory solid or CNS tumors
Efficacy Phase
• To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with conventionally fractionated or hypofractionated radiation among patients with newly diagnosed DIPG
• To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with conventionally fractionated or hypofractionated radiation among patients with newly diagnosed HGG
• To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with re-irradiation in patients with recurrent HGG
• To assess PK of REGN2810 Safety, as measured by the incidence and severity of treatment-emergent adverse events (TEAEs)/immune-related adverse events (irAEs)/adverse events of special interest (AESIs) / serious adverse events (SAEs), deaths, and laboratory abnormalities (grade 3 or higher per version 4.0 of Common Terminology Criteria for Adverse Events (CTCAE v4.0), from initiation of study treatment until 90 days after the last study treatment (or until the patient receives another systemic anticancer therapy, whichever is earlier)
• Tolerability, as measured by the incidence of DLTs from the first dose of REGN2810 through the end of the DLT observation period for cemiplimab given as monotherapy
• PK for REGN2810 given as monotherapy in pediatric patients

Efficacy Phase
• Incidence and severity of TEAEs, irAEs, AESIs, SAEs, deaths, and laboratory abnormalities (Grade 3 or higher per CTCAE v4.0) for REGN2810 given in pediatric patients with newly diagnosed DIPG, newly diagnosed HGG, or recurrent HGG when given in combination with radiation in combination with radiation therapy, from initiation of study treatment until 90 days after the last study treatment (or until the patient receives another systemic anticancer therapy, whichever is earlier). 
• To assess anti-tumor activity of Incidence of DLTs during the DLT observation period for REGN2810 given in combination with radiation in improving overall survival at 12 months (OS12) among patients with newly diagnosed DIPGtherapy
• To assess anti-tumor activity of REGN2810 in combination with radiation in improving progression-free survival at 12 months (PFS12) among patients with newly diagnosed HGG
• To assess anti-tumor activity of REGN2810 in combination with radiation in improving OS12 among patients with recurrent HGG

Secondary Endpoints (1)

Phase 1
• To assess anti-tumor activity of REGN2810 monotherapy as identified by objective response in children with recurrent or refractory solid or CNS tumors
• To assess immunogenicity

Efficacy Phase
• To assess safety and tolerability profiles of REGN2810 PK for REGN2810 given as given in combination with conventionally fractionated or hypofractionated radiation among patients with newly diagnosed DIPGradiation therapy in pediatric patients
• Overall survival at 12 months (OS12) among newly diagnosed DIPG patients and recurrent HGG patients, respectively.
   OS is defined as the time from randomization to the date of death due to any cause. A patient who has not died will be censored at the last date that patient is documented to be alive.
• Progression-free survival at 12 months (PFS12) among newly diagnosed HGG patients.
   PFS is defined as the time from randomization to the date of the first documented tumor progression, as determined per RANO/iRANO criteria, or death due to any cause. Patients will be censored according to rules listed below:
− Patients without a documented tumor progression or death will be censored on the date of their last evaluable tumor assessment.
− Patients without a documented tumor progression or death before initiation of another anti-tumor therapy will be censored on the date of their last evaluable tumor assessment prior to or on the date of new anti-tumor therapy.
− Patients who withdraw consent before taking any study treatment, and as a consequence have no post-baseline tumor assessment, will be censored at the date of randomization
− Patients without any evaluable tumor assessments after randomization and did not die will be censored on the date of randomization.

Secondary Endpoints (2)

Phase 1
• Objective response rate (ORR). ORR is defined as the percentage of patients who have a best overall response (BOR) of confirmed complete response (CR) or partial response (PR).
   BOR is defined as the best overall response, as determined per RECIST 1.1/irRECIST criteria for solid tumors and per RANO/iRANO criteria for CNS tumors, between the date of first dose of REGN2810 and the date of the first objectively documented progression or     the date of receiving another anticancer systemic therapy, whichever comes first.
• Anti-drug antibody (ADA) assessments for REGN2810 given as monotherapy

Efficacy Phase
• To assess safety and tolerability profiles of REGN2810 given in combination with conventionally fractionated or hypofractionated radiation among patients with newly diagnosed HGG
• To assess safety and tolerability profiles of ADA assessments for REGN2810 given in combination with re-irradiation among patients with recurrent HGGradiation therapy

Exploratory Endpoints

Phase 1 and Efficacy Phase
• Quality of Life (QoL), as measured using Pediatric Quality of Life (PedsQL) for younger age group 2 to <18 years
• QoL, as measured using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) for older age group 18 to 25 years.
• Circulating tumor cells, biomarker data, circulating cytokines, and peripheral blood mononucleated cells (PBMC), tumor expression of PD-L1 for biomarker and correlative studies

Sample Size
In Phase 1, a minimum of 30 patients will be enrolled. This will include at least 6 patients in the age 0 to <12 recurrent/refractory tumor cohort (Cohort A), at least 3 patients in the age 12 to <18 recurrent/refractory tumor cohort (Cohort B), at least 6 patients in the age 0 to <12 CNS tumor cohort (Cohort C), and at least 3 patients in the age 12 to <18 CNS tumor cohort (Cohort D), as well as 6 additional patients (at the corresponding identified RP2D) in each of the solid tumor cohorts.
In the Efficacy Phase, a minimum of 30 patients will initially be enrolled as part of the 3+3 design to assess the safety of the anticipated RP2D of REGN2810 in combination with either conventional or hypofractionated radiation. This will include at least 6 patients in the age 3 to <12 newly diagnosed DIPG (Cohort E; 3 in each treatment arm), at least 6 patients in the age 12 to 25 newly diagnosed DIPG cohort (Cohort F; 3 in each treatment arm), at least 6 patients in the age 3 to <12 newly diagnosed HGG cohort (Cohort G; 3 in each treatment arm), at least 6 patients in the age 12 to 25 newly diagnosed HGG cohort (Cohort H; 3 in each treatment arm), at least 3 patients in the age 3 to <12 recurrent HGG cohort (Cohort I), and at least 3 patients in the age 12 to 25 recurrent HGG cohort (Cohort J).
Once the RP2D of REGN2810 is confirmed for a given cohort (and treatment arm, where applicable), additional patients will be enrolled as part of expansion. During expansion, the total number of patients enrolled will be based on treatment regimen, irrespective of patient age or cohort. Additional patients will be enrolled until at least 20 evaluable patients are reached, based on a Simon two-stage design, in each of the following pooled treatment arms:

Newly diagnosed DIPG with conventionally fractionated radiation + REGN2810 (DIPG Arm 1)
• Newly diagnosed DIPG with hypofractionated radiation + REGN2810 (DIPG Arm 2)
• Newly diagnosed HGG with conventionally fractionated radiation + REGN2810 (Newly Diagnosed HGG Arm 1)
• Newly diagnosed HGG with hypofractionated radiation + REGN2810 (Newly Diagnosed HGG Arm 2)
• Recurrent HGG with reirradiation + REGN2810 (Recurrent HGG Arm 1)

Once safety for each combination of indication and treatment regimen is established, additional patients will be enrolled until a total of 20 evaluable patients are reached based on the Simon’s two-stage designIn total, a minimum of 100 patients (20 patients per pooled treatment arm at the respective confirmed RP2D) will be enrolled in the Efficacy Phase. The justification of sample size is described in the protocol.

Sample Size Justification and Accrual Rate

The most recent Children’s Oncology Group study that treated children with newly diagnosed DIPG with a combination of radiation therapy and temozolomide resulted in a mean OS12 rate of 40% (Standard Deviation ± 6.5%)67+/-6.5%)67. We will apply these findings as historical controls for our DIPG cohort treatment arms. The null hypothesis for each DIPG treatment arm is an OS12 of 40% , with a target alternative hypothesis of 70% OS12. Note that although DIPG patients cohorts will be randomized equally between arms 1 and 2 but the , evaluations will be done within each arm as this trial is not powered for comparisons between arms.

Within each DIPG radiation arm, 20 eligible and evaluable DIPG patients will be randomized in order to achieve at least 80% power to detect the above absolute increase of 30% in OS12 within an arm using a one-sided 0.05 level exact binomial test. This phase of the study will follow a two-stage design , where initially 7 patients are entered at the first stage in each arm. If no more than 3 deaths occur within 12 months in the initial cohort, the study will move to the second stage. In each arm, an additional 13 eligible patients will be randomized. If at the first stage, 4 or more patients die within 12 months in an arm, that arm will be temporarily closed and a detailed review performed. The study team together Regeneron and its delegates will determine if accrual will continue or enrollment be stopped in this arm. The arm will be considered a success (reject the associated null hypothesis) if at least 12 of the 20 patients survive beyond 12 months. There is a 71% chance of stopping early under the null hypothesis under this two-stage design. To allow for ineligibility, we anticipate there may be an additional 1-2 patients enrolled in this cohort overall to achieve the target number of eligible and evaluable patients.

It is expected that the study will not pause after the first stage accrual goals are met for each cohort, but that the first stage patients will be monitored with respect to the first stage futility rule above. However, given the requirement of 12 months of follow-up to determine the OS12 endpoint for each patient, should the accrual to the first stage be rapid and there is insufficient follow-up in the first stage cohort to obtain an OS signal before continuing to accrue to the second stage, consideration will be given to pausing accrual in order to gather information at the first stage. Furthermore, if before expansion to the second stage there is clear evidence for a need to pause accrual (eg, 2 or 3 deaths observed in the first cohort) then the study will halt accrual until it can be confirmed that it is warranted to move to the second stage.

The most recent Children’s Oncology Group study that treated children with newly diagnosed HGG with a combination of radiation therapy, lomustine, and temozolomide resulted in a mean PFS12 rate of 49%6849%68. We will apply these findings as historical controls for our newly diagnosed HGG cohorttreatment arms. The null hypothesis for each arm is a PFS12 of 50% with a target alternative hypothesis of 80% PFS12. Note that although HGG patients cohorts will be randomized equally between arms 1 and 2 but the , evaluations will be done within each arm as this trial is not powered for comparisons between arms.

The target sample size for this cohort is 20 (Within each newly diagnosed HGG treatment arm, 20 eligible and evaluable newly diagnosed HGG patients at the RP2D total, this will include all age cohorts) level will be randomized in order to maintain 80% power to detect the alternative hypothesis using a one-sided 0.05 level exact binomial test. This phase of the study will also follow a two-stage design where initially 7 patients are entered at the first stage. If no more than 2 patients experience disease progression or death within 12 months in the initial cohort, the study will move to the second stage and an additional 13 patients will be entered. If at the first stage, 3 or more patients experience disease progression or death within 12 months, the arm will be temporarily closed and a detailed review performed. The study team together with Regeneron and its delegates will determine if accrual will continue or enrollment be stopped in this arm. The arm will be considered a success (reject the associated null hypothesis) if at least 14 of the 20 patients do not experience disease progression or death at or beyond 12 months. There is a 77% chance of stopping early under the null hypothesis under this two-stage design. To allow for ineligibility, there may be an additional 1-2 patients enrolled in this cohort overall to achieve the target eligible and evaluable number of patients.

Based on cumulative outcome data from a 20-year systematic review and meta-analysis69meta-analysis69, the cumulative median overall survival over the last decade was 8.5 months for recurrent pediatric HGG, which translates into OS12 of 37.6% under exponential distribution. We assume the OS12 of 40% as null hypothesis and OS12 of 70% as alternative hypothesis. The target sample size for this cohort is 20 eligible all recurrent HGG patients (is 20 eligible and evaluable recurrent HGG patients at the RP2D total, this will include all age cohorts) level in order to maintain 80% power to detect the alternative hypothesis using a one-sided 0.05 level exact binomial test. This phase of the study will also follow a two-stage design where initially 7 patients are entered at the first stage. If no more than 3 deaths occur within 12 months in the initial cohort, the study will move to the second stage and an additional 13 patients will be entered. If at the first stage, 4 or more patients die within 12 months, the arm will be temporarily closed and detailed review performed. The study team together with Regeneron and its delegates will determine if accrual will continue or enrollment be stopped in this arm. The arm will be considered a success (reject the associated null hypothesis) if at least 12 of the 20 patients survive beyond 12 months. There is a 71% chance of stopping early under the null hypothesis under this two-stage design. To allow for ineligibility, there may be an additional 1-2 patients enrolled in this cohort overall to achieve the target number of eligible and evaluable patients.

It is expected that the study will not pause after the first stage accrual goals are met for these cohorts, but that the first stage patients will be monitored with respect to the first stage futility rule above. However, given the requirement of 12 months of follow-up to determine the OS12 or PFS12 endpoint for each patient, should the accrual to the first stage be rapid and there is insufficient follow-up in the first stage cohort to obtain an OS or PFS signal before continuing to accrue to the second stage, consideration will be given to pausing accrual in order to gather information at the first stage. Furthermore, if before expansion to the second stage there is clear evidence for a need to pause accrual (eg, 1 or 2 deaths observed in the first cohort) then the study will halt accrual until it can be confirmed that it is warranted to move to the second stage.

In the event that interim pharmacokinetic analysis indicates serum concentrations below goal trough exposure for any cohort or age group, study investigators along with study sponsors will determine appropriateness of additional dose escalation or expansion cohorts in the phase 1 or efficacy phase of this study.

Criteria to be Evaluable for Efficacy and Toxicit

As per Intention to Treat analyses, any patient who receives at least one dose of REGN2810 will be evaluable for efficacy and toxicity.

As Per Protocol analyses, there will be separate criteria to be considered evaluable for efficacy and DLT. Patients who receive less than 85% of the prescribed dose of REGN2810 or who receive less than the required percentage of radiation during the DLT period within each cohort (as per description and tables below), may not be evaluable for efficacy or toxicity in the Per Protocol analyses (and may be replaced by another enrollee as per replacement criteria).

Due to the known role of radiation in the treatment of newly diagnosed DIPG and HGG, we will require patients receive at least 90% of intended radiation dosing to be evaluable for toxicity or efficacy in the Per Protocol analyses. This includes the following minimum fractions for each newly diagnosed cohort: Cohort

Minimum # of radiation fractions for Per Protocol analyses

Newly diagnosed DIPG

Standard Conventional fractionation

27

Hypofractionation

12

Newly diagnosed HGG

Standard Conventional fractionation

30

Hypofractionation

12

Inclusion Criteria

INCLUSION CRITERIA

To be eligible for this study, all patients must meet the criteria outlined.

Inclusion criteria applicable only to Phase 1 or the Efficacy Phase are provided Performance status criteria can be found in Appendix 1. For mandatory
radiation dose constraints.

The inclusion criteria provided below are to be interpreted literally and cannot be waived.

All Patients (Phase 1 and Efficacy Phase)
 Karnofsky performance status 50 (patients >16 years) or Lansky performance status
 50 (patients 16 years)
 Patients who are unable to walk due to paralysis, but who are able to use a
    wheelchair, will be considered ambulatory for the purpose of assessing performance score
 Life expectancy >8 weeks
 Adequate bone marrow function, defined as:

   a. Peripheral absolute neutrophil count (ANC)

1000/mm3 and,
   b. Platelet count 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for ≥7 days prior to study registration) and,
   c. Hemoglobin ≥8 g/dL (transfusion independent)
 Adequate renal function, defined as:
    a. Creatinine clearance or radioisotope glomerular filtration rate (GFR)

70 mL/min/1.73 m2 or,
   b. Serum creatinine based on age/gender as follows:

  • Adequate Renal Function Defined as:

       a) Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or
       b) A serum creatinine based on age/gender as follows:

  • AgeMaximum Serum Creatinine (mg/dL)
     MaleFemale
    0 to 2 months0.90.9
    2 months to <2 years0.60.6
    2 to <6 years0.80.8
    6 to <10 years11
    10 to <13 years1.21.2
    13 to <16 years1.51.4
    ≥16 years1.71.4
    The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control.
  • Adequate Liver Function Defined as:

       a) Bilirubin (sum of conjugated + unconjugated) 1.5 x upper limit of normal (ULN) for age

          and

       b) SGPT (ALT) 110 U/L and

       c) Serum albumin ≥2 g/dL

  • Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if seizures are well-controlled

Patient or legally authorized representative (LAR) able to understand, and willing to sign, a written informed consent
 

Phase 1

 Age 0 to <18 years

 Diagnosis of recurrent or refractory solid or CNS tumor
 Histologic confirmation of malignancy at original diagnosis or relapse
 Multifocal DIPG will be eligible for Phase 1
 Exception: patients with metastatic spine disease and gliomatosis, as documented
    by diffuse involvement of >2 lobes, are not eligible
 Available tumor tissue from biopsy or resection; archived tissue is acceptable
 Radiation therapy: for solid tumors outside of the CNS, an interval of ≥14 days between
    local palliative radiation therapy and study registration; for CNS tumors, interval of
    ≥12 weeks between radiation therapy and study registration
 Note: these requirements are due to concerns of pseudo-progression in the CNS and
    challenges that may arise from delineating toxicity related to radiation versus drug

 

Efficacy Phase

Newly Diagnosed DIPG (Cohorts E and F) Only
 

 Age 3 to 25 years
 Histological confirmation of newly diagnosed DIPG
 Patients with or without H3K27M mutations are eligible
 Patients with infiltrating astrocytomas within the pons, consistent with DIPG, are 

 Patients with disseminated spine disease are not eligible. Magnetic resonance
    imaging (MRI) of the spine must be performed if the treating physician suspects
    disseminated disease
 Available tumor tissue from biopsy or resection; archived tissue is acceptable
 No prior therapy before study registration
 No prior radiation before study registration
 First study treatment administration ≤28 days from the date of radiographic diagnosis

 

Newly Diagnosed HGG (Cohorts G and H) Only

 Age 3 to 25 years
 Histological confirmation of newly diagnosed high-grade glioma (WHO grade III-IV) within the cerebrum and/or the cerebellum, including but not limited to infiltrating astrocytomas outside of the pons
 Patients with or without H3K27M mutations are eligible
 Patients with disseminated disease anywhere outside of the cerebrum or cerebellum are not eligible
 Patients whose primary diagnosis is high-grade glioma of the spinal cord are not eligible
 Patients with DIPG are excluded from this cohort
 Available tumor tissue from biopsy or resection; archived tissue is acceptable
 No prior therapy before study registration
 No prior radiation before study registration
 First study treatment administration ≤28 days of the date of definitive surgery

 

Recurrent HGG (Cohorts I and J) Only:

 Age 3 to 25 years
 Diagnosis of recurrent high-grade glioma (WHO grade III-IV) within the cerebrum and/or the cerebellum, including but not limited to infiltrating astrocytomas outside of the pons
 Patients with or without H3K27M mutations are eligible
 Recurrent lesions must be treatable within a single radiation field that can meet mandatory radiation dose constraints
 Patients will be limited to first or second recurrence
 Patients with disseminated disease anywhere outside of the cerebrum or cerebellum are not eligible. Patients whose primary diagnosis included high-grade glioma of the spinal cord are not eligible. Patients with DIPG are excluded from
    this cohort
 Histological confirmation of recurrent high-grade glioma (WHO grade III-IV) is
    preferred
 Available tumor tissue from biopsy or resection; archived tissue is acceptable
 Patients must have had previous irradiation as therapy for HGG diagnosis
 Patients are allowed to have undergone prior therapy including surgery, chemotherapy, and radiation therapy. Patients must have fully recovered from acute side effects related to previous anticancer therapies
 Patients must have:
 Had their last fraction of local irradiation to primary tumor ≥6 months prior to study registration; investigators are reminded to review potentially eligible cases to avoid confusion with pseudo-progression
 Had their last dose of myelosuppressive chemotherapy ≥21 days prior to study registration (≥42 days if nitrosourea therapy)
 Had their last dose of hematopoietic growth factor ≥14 days (long-acting growth factor) or ≥7 days (short-acting growth factor) prior to study registration, or beyond the time during which adverse events (AEs) are known to occur
 Had their last dose of biologic (anti-neoplastic agent) ≥7 days prior to study registration, or beyond the time during which AEs are known to occur 
 Had their last dose of monoclonal antibodies ≥21 days prior to study registration

Important note: The eligibility criteria listed above are interpreted literally and cannot be waived.

 

Exclusion Criteria

Exclusion Criteria

The exclusion criteria below apply to all patients in this study, in both Phase 1 and the Efficacy
Phase.

 Patients with bulky metastatic disease of the CNS causing any of the following:
 Uncal herniation or symptomatic midline shift
 Significant, symptomatic mass effect
 Uncontrolled neurological symptoms such as seizures or altered mental status
 Patients with metastatic spine disease and gliomatosis as documented by diffuse involvement of >2 lobes
 Patients who are receiving any other investigational anticancer agent(s)
 Patients on greater than dexamethasone 0.1 mg/kg/day (maximum 4 mg/day) or equivalent dose in alternate corticosteroid, or actively undergoing corticosteroid dose escalation in the last 7 days
 Patients with a history of allogeneic stem cell transplant
 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
 Human immunodeficiency virus (HIV)-positive patients are ineligible if HIV therapy regimen has not been stable for ≥4 weeks, or there is intent to change the regimen within 8 weeks prior to study registration
 Patients who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
 Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immune-related AEs
 Prior treatment with an agent that blocks the PD-1/PD-L1/PD-L2 pathway
 History of pneumonitis within the last 5 years or any history of thoracic radiation
 Patients who have received prior craniospinal irradiation (CSI) or have prior radiation fields that overlap the lung
 History of documented allergic reactions or acute hypersensitivity reaction attributed to agents used in the study
 Patients who have received live vaccines within 28 days (4 weeks) prior to study registration
 Continued sexual activity in males or women of childbearing potential (WOCBP)1 who are unwilling to practice highly effective contraception prior to the initial dose/start of
    the first treatment, during the study, and for at least 6 months after the last dose
    Examples of highly effective contraceptive measures in WOCBP include:

  • Intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; vasectomized partner2; stable use of combined (estrogen and progestogen containing)
  • Hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; and/or sexual abstinence 3,4
  • Male study participants with WOCBP partners are required to use condoms unless they are vasectomized2 or practice sexual abstinence3,4

1- WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Pregnancy testing and contraception are not required for women with documented hysterectomy
      or tubal ligation. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy
2- Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success
3- Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs
      to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient
4- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female
     condom and male condom should not be used together
     WOCBP who are pregnant or breast-feeding. WOCBP must have a negative pregnancy test (serum or urine) within 14 days prior to study registration

Important note: The eligibility criteria listed above are interpreted literally and cannot be waived.