SB-4826 in Adult Participants With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin Lymphomas

Open to people ages 18 years and up

1 - Aged 18 and older.

2- Capable of giving signed informed consent.

3- Phase 1 (Dose-Escalation): Histologically or cytologically confirmed locally advanced or metastatic solid tumor or non-Hodgkin lymphomas. For indolent non-Hodgkin lymphomas, there must be an indication for systemic therapy such as: Local symptoms due to progressive or bulky nodal disease; Threat of or present compromise of normal organ function due to progressive or bulky disease; Presence of systemic B symptoms (ie, fevers, weight loss, night sweats); Presence of symptomatic extranodal disease, such as effusions; Cytopenias due to bone marrow infiltration, autoimmune hemolytic anemia or thrombocytopenia, or hypersplenism; An increase in disease tempo.

4- Phase 2 (Dose-Expansion/ Combination Therapy): Histologically or cytologically confirmed non-Hodgkin lymphomas. For indolent non-Hodgkin lymphomas, there must be an indication for systemic therapy such as: Local symptoms due to progressive or bulky nodal disease; Threat of or present compromise of normal organ function due to progressive or bulky disease; Presence of systemic B symptoms (ie, fevers, weight loss, night sweats); Presence of symptomatic extranodal disease, such as effusions; Cytopenias due to bone marrow infiltration, autoimmune hemolytic anemia or thrombocytopenia, or hypersplenism; An increase in disease tempo. Patients must be planned to receive rituximab as standard of care (on label or medically accepted) treatment for NHL.

5- Participant's malignancy has relapsed after, progressed on, is not a candidate for, is intolerant of, or refuses standard of care therapies.

6- For solid cancer, at least one measurable lesion based on response evaluation criteria in solid tumors (RECIST v1.1).

7- Adequate hematologic parameters unless cytopenia are due to malignancy (i.e. marrow involvement): Hemoglobin ≥ 8 g/dL; Absolute neutrophil count ≥ 1000/microliter or ≥ 750/microliter if Duffy null phenotype; Platelet count ≥ 50,000/microliter.

8- Adequate organ function defined as: Calculated creatinine clearance ≥ 60 mL/min; Serum alanine aminotransferase and aspartate aminotransferase ≤ 1.5 x upper limit of normal; Total bilirubin ≤ 1.5 x upper limit of normal (for participants with known Gilbert's syndrome, direct bilirubin must be ≤ 1.5 x upper limit of normal).

9- All adverse events related to prior therapy or disease (except alopecia) have resolved to grade 2 or less.

10- Life expectancy ≥ 3 months.

11- Eastern Cooperative Oncology Group Performance Status: ≤ 2

12- Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: Is a woman of nonchildbearing potential (WONCBP) OR is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency during the study intervention period and for at least 1 month in the monotherapy group and 12 months in the SB-4826 plus rituximab group. The 1-month timeframe after the last study dose of SB-4826 is a conservative time frame based on the fact that 1 week corresponds to 7 half-lives. Contraception after the last dose of rituximab is required for at least 12 months. The investigator should evaluate the potential for contraceptive method failure (e.g., nonadherence, recently initiated) in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum with sensitivity of at least 25 mIU/mL) within 24 hours before the first dose of study drug.

13- Male Participants: Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 3 months after the last study dose. The 3-month timeframe is based on spermatogenesis (74 days) plus at least 1week after the last study dose of SB-4826 (1 week is approximately 7 half-lives). No precautions are required for rituximab. Male participants must refrain from donating sperm plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR agree to use a male condom when having sexual intercourse with a woman of childbearing potential. Female partners of male participants who are WOCBP are permitted to use hormonal contraception and must have barrier method of contraception. Note: A male participant is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.

1. Inability to take oral medications.
2. Use of systemic cancer therapy (e.g., chemotherapy, immunotherapy, biologic, hormonal therapy) within 21 days or 5 half-lives, whichever is shorter.
3. Palliative radiation within 7 days before first dose of study drug.
4. Use of cellular therapy within 60 days before first dose of study drug.
5. Major surgery within 30 days before first dose of study drug.
6. Prior solid organ transplant.
7. Clinically significant cardiovascular disease including any of the following within 6 months before first dose of study drug: myocardial infarction or coronary artery bypass grafting, unstable angina pectoris, serious cardiac ventricular arrhythmia requiring medication, congestive heart failure per New York Heart Association class III or IV, cerebrovascular accident, or poorly controlled hypertension.
8. History of any other malignancy in the past 2 years other than completely resected nonmelanoma skin cancer or carcinoma in situ of the uterine cervix, anus, prostate, bladder, breast, or indolent malignancies that do not require treatment.
9. History of or current chronic liver disease, such as active viral hepatitis, drug- or alcohol-related liver disease, metabolic dysfunction-associated steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease considered clinically significant by the investigator.
10. Mean resting corrected QT interval using Fridericia's formula > 470 msec.
11. Active infection that necessitates treatment within 14 days of first dose of study drug.
12. Active hepatitis B or hepatitis C infection regardless of viremia.
13. Known history of human immunodeficiency virus infection with viral load >50 copies/ml at the time of screening.
14. Active autoimmune disease requiring >10 mg of prednisone daily or equivalent, disease-modifying antirheumatic drugs, or immunosuppression.
15. Use of medications that are known to be sensitive narrow therapeutic index or moderate sensitive substrates, strong or moderate inhibitors or strong or moderate inducers of cytochrome P450 3A4/5, or sensitive substrates or inhibitors of P-glycoprotein, breast cancer resistant protein, or organic anion-transporting polypeptide 1B1/1B3 within 14 days or 5 half-lives, whichever is longer, before first dose of study drug.
16. Receipt of any live vaccine (e.g., varicella, pneumococcus) within 30 days of first dose of study drug.
17. Receipt of investigational products, including drugs and devices, within 21 days or five half-lives, whichever is shorter, before first dose of study drug.
18. History of Grade 3 or higher immune mediated adverse events that were considered drug related to prior immunotherapy (e.g., checkpoint inhibitors, co stimulatory agents).
19. Known active central nervous system metastases. Participants with previously treated stable brain metastases may participate.