There are 2 parts to this study: Part 1 (dose de-escalation) and Part 2 (dose expansion).

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of lenalidomide in combination with obinutuzumab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) that can be given to patients with diffuse large B cell lymphoma.

The goal of Part 2 of this clinical research study is learn if the dose of lenalidomide found in Part 1 can help to control the disease.

The safety of this drug combination will be studied in both parts.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study phase based on when you join this study. Up to 3 groups of up to 6 participants will be enrolled in Phase 1 of the study, and up to 50 participants will be enrolled in Phase 2.

If you are enrolled in Phase 1, the dose of lenalidomide you receive will depend on when you join this study. The first group of participants will receive the highest dose level of lenalidomide. Each new group will receive a lower dose of lenalidomide than the group before it, if intolerable side effects are seen. This will continue until the most tolerable dose of lenalidomide is found.

If you are enrolled in Phase 2, you will receive lenalidomide at the highest dose that was tolerated in Phase 1.

All participants will receive the same dose of CHOP and obinutuzumab.

Study Drug Administration:

Each study cycle is 21 days.

You will take lenalidomide pills by mouth on Days 1-14 of each cycle.

You will receive obinutuzumab by vein over 3-4 hours on Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycles 2-6.

You will receive cyclophosphamide by vein over about 1 hour on Day 1 of all cycles.

You will receive doxorubicin and vincristine by vein over about 15 minutes each on Day 1 of all cycles.

Study Visits:

Within 3 days before Day 1 of Cycles 1-6:

• You will have a physical exam.
• Blood (about 8-9 teaspoons) will be drawn for routine tests and to check for PBMCs.

One (1) time each week during Cycle 1 and then at any time the doctor thinks it is needed, blood (about 2-3 teaspoons) will be drawn for routine tests.

At the end of Cycle 1 but before the start of Cycle 2, blood (about 6 teaspoons) will be drawn to check for PBMCs.

At the end of Cycle 3 but before the start of Cycle 4, you will have a PET/CT scan.

If you can become pregnant, blood (about 2-3 teaspoons) will be drawn for a pregnancy test 1 time before Cycle 1 and then 1 time during each cycle after that.

Length of Treatment:

You may receive lenalidomide, obinutuzumab, and CHOP therapy for up to 6 cycles. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on this study will be over after follow-up.

End-of-Treatment Visit:

Within 3-4 weeks after your last dose of study drugs:

• You will have a physical exam.
• Blood (about 8-9 teaspoons) will be drawn for routine tests and to check for PBMCs.
• You will have a PET/CT scan.
• If the doctor thinks it is needed, you will have a bone marrow biopsy to check the status of the disease.
• If the doctor thinks it is needed and the tumor is accessible, you will have a core needle biopsy to check the status of the disease. To perform a core biopsy, a sample of tissue is removed using a hollow core needle that has a cutting edge.

Follow-Up:

Every 3 months (+/- 4 weeks) during the first year after the End-of-Treatment Visit and then every 4 months (+/- 9 weeks) during the second year:

• You will have a physical exam.
• Blood (about 2-3 teaspoons) will be drawn for routine tests.
• You will have a PET/CT scan.

This is an investigational study. Lenalidomide is FDA approved and commercially available for the treatment of multiple myeloma (MM) and myelodysplastic syndrome (MDS). Obinutuzumab is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia (CLL). CHOP is FDA approved and commercially available for the treatment of lymphoma and non-Hodgkin's lymphoma.

The combination of lenalidomide, CHOP, and obinutuzumab to treat DLBCL is considered investigational.

Up to 59 participants will be enrolled in this study. All will take part at MD Anderson.

Inclusion Criteria:

1. Confirmed treatment-naïve de novo CD20+ DLBCL, regardless of cell of origin, with Stage II-IV disease, or Stage I disease if 6 cycles of chemotherapy are planned.
2. Measurable disease on cross section imaging that is at least 1.5 cm in the longest diameter and measurable in two perpendicular dimensions
3. Appropriate candidate for systemic immune-chemotherapy such as the standard RCHOP21 6 cycles as determined by the treating physician
4. Age >/=18
5. Adequate organ function (normal cardiac ejection fraction of >45%, serum bilirubin <1.5 mg/dl, AST or ALT </= 5 x ULN, and creatinine clearance > 30 mL/min (Calculated according to Cockcroft - Gault formula) unless due to lymphoma with documentation of normal function prior to onset of lymphoma. In the case of Gilberts Syndrome, or documented liver or pancreatic involvement by lymphoma, the requirement for total bilirubin is </=5.0 mg/dl
6. ANC >1000/mm3, hemoglobin >8.0, and platelets >100,000/mm3. If bone marrow is involved with lymphoma and normal marrow function prior to onset of lymphoma is documented: ANC of >750, any hemoglobin, and platelets of >50,000/mm3.
7. Performance status <3 (unless previous performance status was 0 or 1 and deterioration is due to lymphoma which treating MD expects to reverse with therapy)
8. Consent to potential need for transfusion of blood products
9. Able to give informed consent
10. Ability and willingness to comply with the requirements of the study protocol

Exclusion Criteria:

1. Prior history of low grade lymphoma with transformation to DLBCL. If a patient has a composite diagnosis of DLBCL and low grade without a prior history of lymphoma, they will not be considered ineligible.
2. Pregnant or lactating females
3. Symptomatic CNS lymphoma involvement
4. Significant comorbidity (cirrhosis, severe coronary artery disease, significant psychiatric illness, or other that may compromise the ability to safely administer the therapy at the discretion of the primary investigator)
5. HBV: Patients with positive serology for Hepatitis B defined as positivity for HBsAg or anti-HBc. Patients who are positive for anti-HBc may be considered for inclusion in the study on a case-by-case basis if they are hepatitis B viral DNA negative and are willing to undergo ongoing HBV DNA testing by real-time PCR. Patients with positive serology may be referred to a hepatologist or gastroenterologist for appropriate monitoring and management.
6. Hepatitis C (HCV): Patients with positive hepatitis C serology unless HCV RNA is confirmed negative and may be considered for inclusion in the study on a case-by-case basis.
7. Known HIV or HTLV infection
8. Previous malignancy with diagnosis or suspicion of recurrence within the past 2 years, not including non-melanoma skin cancers or in situ malignancies.
9. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
10. Known hypersensitivity to any of the study drugs
11. Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (related to the completion of the course of antibiotics) within 4 weeks before the start of Cycle 1
12. Major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis
13. Fertile men or women of childbearing potential unless 1) surgically sterile or 2) using an adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly.
14. Effective contraception is required while receiving obinutuzumab. For women, effective contraception is required to continue for >/= 12 months after the last dose of obinutuzumab. For men, effective contraception is required to continue for 3 months after the last dose of obinutuzumab treatment.
15. Vaccination with a live vaccine a minimum of 28 days prior to the start of treatment
16. Peripheral neuropathy >/= Grade 2
17. Subjects who are unwilling to take VTE prophylaxis

up to 4.5 years

4 patients died when already off-study, these deaths were after disease progression.