LP-168 and Obinutuzumab for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Variants of This

Inclusion Criteria: 1. Diagnosis of CLL or SLL meeting criteria established in the 2018 iwCLL criteria and requiring treatment. Patients with variation in flow cytometry findings will be allowed to enroll if cytogenetics and/or mutational studies are supportive of CLL/SLL variant. a) Note: Variation in flow cytometry is defined as patients who have atypical immunophenotyping for CLL (CD5 negative, CD23 negative or surface expression of CD79b that is bright ) but clinically behave like CLL (leukocytosis, lymphadenopathy and splenomegaly) and have the FISH/Cytogenetics translocations(del 13q, trisomy 12, Del11q) or genomic features (XPO1, NOTCH1, SF3B1, FBXW7, MYD88, BIRC3, TRAF3, NFKBIE, SAMHD1, POT1, HIST1H1E, CHD2, ZMYM3, EGR2 and others) that are suggestive of CLL. 2. Meet the criteria for inclusion into at least one of the following 2 cohorts: 1. Cohort 1: One or more prior therapies for CLL/SLL including BCL2 inhibitor (BCL2i), and/or chemotherapy and/or BTK inhibitor (BTKi). • Note: Patients can be eligible if their CLL/SLL has been non-responsive to a covalent and noncovalent BTKi. Patients intolerant to BTKi whose disease becomes resistant to a second one are eligible to enroll. Prior treatment with CD20 will not be exclusionary. 2. Cohort 2: Treatment with a prior BTKi (covalent and noncovalent) and have a BTK gatekeeper mutation in the T474 coordinate. 3. Age ≥18 years. 4. ECOG performance status ≤2 (or Karnofsky ≥60%, see Appendix A). 5. Patients must have adequate organ and marrow function as defined below: 1. ANC ≥1,000/mcL, unless if neutropenia is due to underlying CLL bone marrow disease. 2. Platelets ≥ 50,000/ µL unless if thrombocytopenia is due to underlying CLL bone marrow disease then platelets of ≥20,000 is acceptable 3. Total bilirubin ≤1.5 x ULN (excepting Gilbert's syndrome, who may have a bilirubin \> 1.5 × ULN, per discussion between the Investigator and the UC PI). 4. AST and ALT ≤2.5 × ULN. 5. Estimated glomerular filtration rate (by Modification of Diet in Renal Disease \[MDRD\]) or Chronic Kidney Disease Epidemiology \[CKD-EPI\]) ≥ 30 mL/min 6. Women of childbearing potential and non-sterile males must practice at least 1 of the following methods of birth control with their partner(s) throughout the study and for 30 days after discontinuing study drug: 1. Total abstinence from sexual intercourse as the preferred lifestyle of the patient; periodic abstinence is not acceptable. 2. Surgically sterile partner(s) by vasectomy, bilateral orchiectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy. 3. Intrauterine device. 4. Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at least 1-month prior to study drug administration. 7. Women of childbearing potential must have a negative pregnancy result as follows: At Screening on a serum sample obtained within 7 days prior to the first study drug administration. If a urine pregnancy test at any timepoint during the study is positive or indeterminate, a serum pregnancy test will be performed for confirmation. 8. Non-sterile males must refrain from sperm donation, from initial study drug administration until 30 days after the last dose of study drug. 9. Able to provide informed consent. Exclusion Criteria: 1. Patients with active Richter's transformation. 2. Patient has received any of the following therapies within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug, or has not recovered to ≤ Grade 1 clinically significant adverse effect(s)/toxicity(s) of the previous therapy (other than alopecia): 1. Any anti-cancer therapy including chemotherapy, biologic or immunotherapy, radiotherapy, etc. 2. Any investigational therapy, including targeted small molecule agents. 3. For patients who come off BCR antagonist treatment (BTK inhibitors, PI3K inhibitors, etc.), allow washout for 5 half-lives as these patients progress quickly after treatment discontinuation and then remain eligible (steroids may be given during the washout to allow for disease control, see d below for details). 4. When a patient's intercurrent health condition would require short term steroid use this should be discussed with the Investigator in consultation with the Medical Monitor. Steroids are allowed for disease control in those R/R patients when use is limited to 2-3 days to allow for control of the underlying disease. Steroids may be given during the washout to allow for disease control. 3. Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous, in the opinion of the Investigator. 4. Patients who require anti-coagulation with warfarin or equivalent Vitamin K antagonist. 5. Major surgery within 14 days prior to the first dose of study drug. 6. Patients who have received the following medications or therapies within 5 half-lives or 14 days, whichever is shorter, prior to the first dose of study drug: 1. Steroid therapy (at dosages equivalent to prednisone \>20 mg/day) for anti- neoplastic intent (except as noted in exclusion criterion #2). 2. Cytochrome P450, family 3, subfamily A (CYP3A4) strong inhibitors and strong CYP2C8 inducers/inhibitors (see the list in Appendix B) 3. Strong CYP3A4 inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort (Appendix B) 4. There is a 28-day washout period required for patients who have had prior CAR T treatment if there is no evidence of cytokine release syndrome (CRS) or other AEs related to the CAR T treatment per discussion with the UC PI; reduced washout period may be acceptable after discussion with UC PI. 5. Drugs that are substrates of MATE1 and MATE2-K should be avoided or substituted for other medications if possible. Use of these (if done) must be discussed with the PI of the study. (Appendix D). 7. Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or Star fruit within 3 days prior to the first dose of study drug. 8. Patient requires treatment with systemic acid-reducing agents, H2 blocking agent and proton pump inhibitors, with the following exceptions: 1. Proton pump inhibitors should be discontinued at least 7 days or at least 5-half-lives (whichever is shorter) prior and held throughout the study. 2. If concurrent use of an H2 blocking agent is necessary, it must be administered only between 2 and 3 hours after the dose of LP-168. If not taken during this time, the dose of H2 blocking agents should not be taken again until 2 - 3 hours after the next dose of LP-168. 3. If concurrent use of a local antacid is necessary, it must be administered 2 or more hours before and/or 2 or more hours after the dose of LP-168. 9. Patient has clinically significant screening electrocardiogram (ECG) abnormalities including: 1. 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, and corrected QT interval (QTcF) ≥ 480ms (calculated per Fridericia's formula \[QTcF = QT/RR (1/3)\]). 2. For patients with presence of right bundle branch block (RBBB) or left bundle branch block (LBBB), cardiology review is needed to correct QTcF calculation using Sponsor recommended formula (Simplified Formula for Bundle Branch Block). See Appendix C. 3. Other clinically significant ECG abnormalities per PI discretion. 10. Patient has significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 180 days prior to the first dose of study drug, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification or left ventricular ejection fraction ≤ 40%. 11. Patient has a history of stroke or intracranial hemorrhage within 180 days prior to the first dose of study drug. 12. Patients who have undergone autologous/allogeneic hematopoietic stem cell transplantation (HSCT) therapy within 60 days of the first dose of LP-168, or patients on immunosuppressive therapy post-HSCT at the time of Screening, or currently with clinically significant graft-versus-host disease (GVHD) as per treating physician (patients in relapse after allogeneic transplantation must be off treatment with systemic immunosuppressive agents for at least 4 weeks). The use of topical steroids and/or up to 20 mg/day prednisone or equivalent systemic steroids for ongoing GVHD is permitted. 13. Pregnant women, those planning to become pregnant during the study, and/or breastfeeding women are ineligible for participation. 14. Patients with known malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 15. Known hypersensitivity to any of the components of LP-168 (see Investigators Brochure for a list of components). 16. Patients with active bleeding disorder. a) NOTE: Von Willebrand's disease or hemophilia will not be excluded if patient is on treatment and well controlled. 17. Patient exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: 1. Uncontrolled active systemic infection (bacterial, fungal, viral); 2. Known poorly controlled (defined as less than 200 CD4 count) human immunodeficiency virus (HIV) or active hepatitis B or C infection (active hepatitis B defined as HBsAg positive, or HBcAb positive with detectable HBV DNA load; active hepatitis C defined as HCV antibody positive with HCV RNA positive) 3. Unexplained fever \> 38.3°C within 7 days prior to the first dose of study drug administration (if the fever is considered attributed to the patient's malignancy or an explained infection, the Patient may be enrolled at the discretion of the Investigator). 18. Patient has a history of other active malignancies within the past 1 year prior to study entry, with the exception of: 1. Breast cancer or prostate cancer on endocrine therapy with stable disease. 2. Continuation of maintenance therapy in patients with adequately treated malignancy. 3. Cancer with expected survival of 2 years or more or that will not confound evaluation of LP-168 treatment. 4. Adequately treated in situ carcinoma of the cervix uteri. 5. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin. 6. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. 7. Patients with active CNS involvement can be enrolled per Investigator discretion; patients with significant clinical symptoms, including any that require treatment with high dose steroid, will be excluded.