Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase 1 Study of ACTR707, an Autologous T Cell Product, in Combination With Rituximab, in Subjects With Relapsed or Refractory CD20+ B Cell Lymphoma
Brief Summary: This is a phase 1, multi-center, single-arm, open-label study evaluating the safety and anti-lymphoma activity of an autologous T cell product (ACTR707) in combination with rituximab in subjects with refractory or relapsed CD20+ B cell lymphoma.


Options:
A: Inclusion Criteria:

* Histologically confirmed pediatric mature B-cell non-Hodgkin lymphoma (B-cell NHL) including the following subtypes; Burkitt lymphoma/ Burkitt leukemia (BL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), and follicular lymphoma (FL) Note: Patients with B-cell NHL associated with Nijmegen breakage syndrome will be allowed.
* Patients \<25 years of age and weighing at least 6 kg at the time of screening
* Patients who have relapsed after one or more prior therapies (can include allogeneic and autologous hematopoietic stem cell transplant) or are primary refractory (have not achieved a CR or PR after the first line of therapy)
* Measurable disease by radiological criteria in all patients at the time of screening. Patients with Burkitt leukemia who don't meet radiological criteria must have bone marrow involvement of \>25% by local assessment of bone marrow aspirate and/or biopsy.
* Karnofsky (age ≥16 years) or Lansky (age \<16 years) performance status ≥60.
* Adequate bone marrow reserve without transfusions (transfusion \>2 weeks prior to laboratory assessment is allowed) defined as:

  1. Absolute neutrophil count (ANC) \>1000/mm3
  2. Platelets ≥50000//mm3
  3. Hemoglobin ≥8.0 g/dl
* Adequate organ function defined as:

  1. a serum creatinine (sCR) based on gender/age as follows: Maximum Serum Creatinine (mg/dL) Age Male Female

     1 to \<2 years 0.6 0.6 2 to \<6 years 0.8 0.8 6 to \<10 years 1.0 1.0 10 to \<13 years 1.2 1.2 13 to \<16 years 1.5 1.4

     ≥16 years 1.7 1.4
  2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN) for age
  3. Total bilirubin \<2 mg/dL (for Gilbert's Syndrome patients total bilirubin \<4 mg/dL)
  4. Adequate pulmonary function

  i. Oxygen saturation of \>91% on room air ii. No or mild dyspnea (≤Grade 1)
* Must have a leukapheresis material of non-mobilized cells accepted for manufacturing.

Exclusion Criteria:

* Prior gene therapy or engineered T cell therapy.
* Prior treatment with any anti-CD19 therapy.
* Allogeneic hematopoietic stem cell transplant (HSCT) \<3 months prior to screening and ≤4 months prior to infusion.
* Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) in patients who received prior allogeneic HSCT.
* Prior diagnosis of malignancy other than study indication, and not disease free for 5 years.
* Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
* Presence of active hepatitis B or C as indicated by serology.
* Human Immunodeficiency Virus (HIV) positive test.
* Active neurological autoimmune or inflammatory disorders not related to B cell NHL (eg: Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)
* Active central nervous system (CNS) involvement by malignancy.
* Patients with B-cell NHL in the context of post-transplant lymphoproliferative disorders (PTLD) associated lymphomas.
B: Inclusion Criteria:

* Relapsed or refractory CD19+ B-cell lymphoma or leukemia.
* Measurable disease.
* Performance status ECOG 0-2.
* \>18 years old.
* Fertile females/males must consent to use contraceptives during participation of the trial.
* Signed informed consent.

Exclusion Criteria:

* Any significant medical or psychiatric illness that would prevent the patient from giving informed consent or from following the study procedures.
* Patients with primary CNS lymphoma.
* Known human immunodeficiency virus (HIV) infection.
* Active and/or severe infection (e.g. tuberculosis, sepsis and opportunistic infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection).
* Other serious underlying medical conditions, which, in the Investigator's judgment, could impair the ability of the patient.
* Treatment with an investigational product within 30 days prior to enrollment, or at least 5 half lives of that drug, which is longest.
* Patients that do not consent to that tissue and blood samples are stored in a biobank.
* Pregnancy
C: Inclusion Criteria:

* signed written informed consent obtained prior to study procedures
* histologically-confirmed relapsed or refractory CD20+ B-cell lymphoma of one of the following types, with documented disease progression or recurrence following the immediate prior therapy: DLBCL (regardless of cell of origin or underlying molecular genetics), MCL, PMBCL, Gr3b-FL, TH-FL (prior dx of FL before transforming to DLBCL).
* biopsy-confirmed CD20+ expression of the underlying malignancy with disease progression following immediate prior therapy
* at least 1 measurable lesion on imaging.
* must have received adequate prior therapy for the underlying CD20+ B-cell lymphoma, defined as an anti-CD20 mAb in combination with an anthracycline-containing chemotherapy regimen (i.e. chemo-immunotherapy) and at least one of the following:

  * biopsy-proven refractory disease after frontline chemo-immunotherapy
  * relapse within 1 year from frontline chemo-immunotherapy and ineligible for autologous hematopoietic stem cell transplant (auto-HSCT)
  * for subjects with DLBCL, PMBCL, and Gr3b-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT
  * for subjects with TH-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT. At least 1 prior regimen with an anti-CD20 mAb in combination with chemotherapy is required following documented transformation
  * for subjects with MCL (confirmed with cyclin D1 expression or evidence of t(11;14) by cytogenetics, fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR): relapsed or refractory disease after at least 1 prior regimen with chemo-immunotherapy (prior auto-HSCT is allowable)
* ECOG 0 or 1
* life expectancy of at least 6 months
* platelet count greater than 50,000/µL

Exclusion Criteria:

* known active central nervous system (CNS) involvement by malignancy.
* prior treatment as follows:

  * alemtuzumab within 6 months of enrollment
  * fludarabine, cladribine, or clofarabine within 3 months of enrollment
  * external beam radiation within 2 weeks of enrollment
  * mAb (including rituximab) within 2 weeks of enrollment
  * other lymphotoxic chemotherapy (including steroids except as below) within 2 weeks of enrollment
  * experimental agents within 3 half-lives prior to enrollment, unless progression is documented on therapy
* clinically significant cardiac disease
* clinically significant active infection
* clinically significant CNS disorder
* clinical history, prior diagnosis, or overt evidence of autoimmune disease
* known bone marrow involvement due to underlying malignant disease, in dose-escalation phase only
D: * INCLUSION CRITERIA:

  1. Patient must have a cluster of differentiation 19 (CD19)-expressing B-cell lymphoma. Patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and diffuse large B-cell lymphoma transformed from follicular lymphoma must have measurable disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab.
  2. Confirmation of diagnosis of B-cell malignancy and positivity for CD19 confirmed by the Laboratory of Pathology of the National Cancer Institute (NCI). The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood, fine needle aspirates and bone marrow samples.
  3. Patients must have indications for treatment for their B-cell malignancy at the time of enrollment on this trial.
  4. Greater than or equal to 18 years of age and less than or equal to age 70.
  5. Willing to sign a durable power of attorney.
  6. Able to understand and sign the Informed Consent Document.
  7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  8. Life expectancy of greater than three months.
  9. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
  10. Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  11. Serology:

      * Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.).
      * Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive. Then patients must be tested for the presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
  12. Hematology:

      * Absolute neutrophil count greater than or equal to 1000/mm\^3 without the support of filgrastim.
      * Platelet count greater than or equal to 50,000/mm\^3.
      * Hemoglobin greater than 8.0 g/dl.
      * Lymphocyte count less than or equal to 4,000/ mm\^3
  13. Chemistry:

      * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 5 times the upper limit of normal.
      * Serum creatinine less than or equal to 1.6 mg/dl
      * Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl
  14. More than three weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patient toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
  15. Normal cardiac ejection fraction and no evidence of pericardial effusion as determined by an echocardiogram.

EXCLUSION CRITERIA:

1. Patients that require urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
2. Patients that have active hemolytic anemia.
3. Patients with active brain metastases, or with a history of any central nervous system (CNS) metastases or cerebrospinal fluid malignant cells.

   Note: patients who are asymptomatic but are found to have malignant cells in the cerebrospinal fluid (CSF) on lumbar puncture prior to treatment will be considered eligible.
4. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
5. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
7. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
8. Concurrent systemic steroid therapy.
9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
10. History of allogeneic stem cell transplantation
11. Patients with cardiac atrial or cardiac ventricular lymphoma involvement.

Screening Evaluation:

Within 4 weeks prior to starting the chemotherapy regimen:

1. Complete history and physical examination, including, weight and vital signs, noting in detail the exact size and location of any lesions that exist. (Note: patient history may be obtained within 8 weeks.)
2. Chest x-ray
3. Electrocardiography (EKG)
4. Baseline computed tomography (CT) of the chest, abdomen and pelvis, positron emission tomography (PET) scan, and brain magnetic resonance imaging (MRI) to evaluate the status of disease. Additional scans and x-rays may be performed if clinically indicated based on patient signs and symptoms.
5. HIV antibody titer and Hepatitis B surface antigen (HbsAG) determination, and anti HCV, (Note: May be performed within 3 months of the chemotherapy start date).
6. Anti cytomegalovirus (CMV) antibody titer, herpes simplex virus (HSV) serology, and Epstein-Barr virus (EBV) panel (Note: patients who are known to be positive for any of the above do not need to be retested; may be performed within 3 months of chemotherapy start date)
7. Patients with a left ventricular ejection fraction (LVEF) of less than or equal to 55% will not proceed to treatment (Note: may be performed within 8 weeks of treatment).
8. Cluster of differentiation 19 (CD19) staining of malignant cells by immunohistochemistry or flow cytometry (testing is permitted to be conducted at any time prior to this point).
9. All patients must have a T cells, B cells, and natural killer cells (TBNK) for Peripheral blood cluster of differentiation 3 (CD3) count and CD19#.
10. Patients with a history of leptomeningeal disease, or signs/symptoms suggestive of leptomeningeal involvement, or with symptoms of central nervous system malignancy such as new onset severe headaches, neck stiffness, or any focal neurologic findings on physical exam will have lumbar puncture for examination of cerebral spinal fluid.
11. Patients may undergo lumbar puncture (LP) for flow cytometry of the CSF in order to assess the presence of CD19 positive lymphocytes for potential correlation with neurologic toxicity. Patients who have no neurologic symptoms at the time of LP will be eligible for enrollment regardless of the results of the flow cytometry.

    Within 14 days prior to starting the chemotherapy regimen:
12. Chem 20: (Sodium (Na), Potassium (K), Chloride (Cl), Total carbon dioxide (CO2) (bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/glutamic pyruvic transaminase (GPT), AST/glutamic oxaloacetic (GOT), Total Bilirubin, Direct Bilirubin, lactate hydrogenase (LD), Total Protein, Total creatine kinase (CK), Uric Acid)
13. Thyroid panel
14. Complete blood count (CBC) with differential and platelet count
15. Prothrombin time (PT)/partial thromboplastin time (PTT)
16. Urinalysis and culture, if indicated

    Within 7 days prior to starting the chemotherapy regimen:
17. Beta-human chorionic gonadotropin (βHCG) pregnancy test (serum or urine) on all women of child-bearing potential
18. ECOG performance status of 0 or 1

Answer: C