Study of LVGN3616 and LVGN6051±LVGN7409 in Combination With Nab-Paclitaxel or Bevacizumab and Cyclophosphamide in Metastatic Solid Tumors

Inclusion Criteria:

To be eligible for this trial, patients must meet all the following eligibility criteria.

• Patients must have histologically confirmed metastatic solid tumors withpre-identified molecular profiling in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, either refractory to standard therapy or for which noeffective standard therapy that increases survival for at least 3 months isavailable, or they declined standard of care therapy (the treating physician needsdocument reasons for a patient to decline standard of care therapy and providejustification for participating this study in the medical record, which will berecorded in eCRF).

• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

• Male or female aged ≥18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

• Adequate organ functions as defined below:

• Absolute neutrophil count (ANC) ≥ 1,500 /μL.

• Hemoglobin (Hb) ≥ 8.5 g/dL.

• Platelets ≥ 100,000 /μL for nab-paclitaxel or ≥ 75,000 /μL forcyclophosphamide.

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN); or total bilirubin < 3.0 ×ULN with direct bilirubin ≤ ULN in patients with well documented Gilbert'sSyndrome.

• ALT and AST ≤ 2.5 × ULN.

• Serum albumin ≥ 3 g/dL.

• Urinalysis ≤ 1 proteinuria, or urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤ 1 g (apply to bevacizumab-basedregimens only).

• PT/INR or partial thromboplastin time (PTT) test < 1.3 × the laboratory ULN ifnot on therapeutic anticoagulation.

• Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance (CrCl) ≥ 45mL/min by the Cockcroft-Gault method* or 24-hour urine collection.

• CrCl = (140-age) x (weight/kg) x Fa / (72 x serum creatinine mg/dL). ^awhere F= 0.85 for females and F=1 for males

• Women of child-bearing potential (WOCBP) must have a negative serum pregnancy testwithin 3 days prior to initiation of therapy (C1D1) and must agree to use effectivebirth control during the study prior to the first dose and for at least 6 monthsafter the last dose. Female patients are not considered to be of child-bearingpotential if they are post-menopausal (no menses for 12 months without analternative medical cause) or permanently sterile (hysterectomy, bilateralsalpingectomy, or bilateral oophorectomy). Male patients must agree to abstain oruse barrier contraception (i.e., condoms) and avoid sperm donation for the durationof the study and for 6 months after treatment stops.

• Ability to read and fully understand the requirements of the trial, willingness tocomply with all trial visits and assessments, and willingness and ability to sign aninstitutional review board (IRB)-approved written informed consent document (ICD).Patients with Impaired Decision-Making Capacity (IDMC) must have a close caregiveror Legally Authorized Representative (LAR). For remote and In-person consenting, wewill follow the Office of Clinical Research SOP:04 Informed Consent Process.

• Any prior palliative radiation must have been completed at least 7 days prior to thestart of study drugs, and patients must have recovered from any acute adverseeffects prior to the start of study treatment (Radiotherapy for extended fieldwithin 2 weeks or limited field radiotherapy within 1 week).

• Fridericia's corrected QT interval (QTcF =QT/∛(60/HR) ) ≤ 460 milliseconds (ms) formales and ≤ 480 ms for females on ECG conducted at rest during Screening.

Note: Patients with an atrioventricular pacemaker or other condition (for example, right bundle branch block) that renders the QT measurement invalid are an exception and this criterion does not apply.

• Agreeing to provide an archival tissue block, or 10 formalin-fixed paraffin-embedded (FFPE) slides if available.

• Prior treatment with immunotherapy, taxane, VEGF inhibition or cyclophosphamide isallowed. However, prior immunotherapy with anti-PD1/PD-L1 plus a CD137 agonist or aCD40 agonist is not allowed.

Exclusion Criteria:

Patients who meet any of the following criteria will be not eligible for the study:

• Any treatment specifically for systemic tumor control given within 3 weeks beforethe initiation of therapy; within 2 weeks if cytotoxic agents were given weekly,within 6 weeks for nitrosoureas or mitomycin C; within 5 half-lives for targetedagents with half-lives and pharmacodynamic effects lasting < 5 days; or failure torecover from toxic effects of any previous therapy. A drug that has not receivedregulatory approval for any indication within 14 or 21 days of treatment for anon-myelosuppressive or myelosuppressive agent, respectively: patients must recoverfor previous cancer therapy, and are ready to proceed with further cancer therapy.

• Uncontrolled intercurrent illness including but not limited to:

• ongoing or active infection requiring intravenous antibiotics

• symptomatic congestive heart failure (New York Heart Association Class III orIV)

• history of myocardial infarction, unstable angina, stroke or transient ischemicattack within 6 months before study enrollment

• lesions invading or encasing any major blood vessels and cavitating pulmonarylesion(s) or known endotracheal or endobronchial disease manifestation.Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hgsystolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment (apply to bevacizumab-based regimens only)

• history or current evidence of uncontrolled ventricular arrhythmia

• congenital long QT syndrome, or any known history of torsade de pointes, orfamily history of unexplained sudden death

• clinically significant bleeding or active gastric or duodenal ulcer

• chronic diarrhea diseases considered to be clinically significant byinvestigator

• Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominalabscess within 6 months before first dose of study treatment, or anygastrointestinal disorders associated with a high risk of perforation orfistula formation

• other severe acute or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation, ormay interfere with the interpretation of study results, and in the judgment ofthe Investigator would make the patient inappropriate for entry into this studyNote: Subjects with a diagnosis of incidental, subsegmental pulmonary embolismor deep vein thrombosis are allowed if stable, asymptomatic, and treated with astable dose of permitted anticoagulation for at least 1 week before first doseof study treatment.

• Unresolved clinically significant Grade 1 or higher toxicity from prior therapy.

• History of allergic reactions to the study drugs, or any component of the products.

• Presence of other active invasive cancers that requires active treatment other thanhormonal therapy.

• Having not recovered from a major surgical procedure or significant traumatic injury (i.e., still needing additional surgical or medical care for these issues): majorsurgical procedures ≤ 28 days of treatment entry, or minor surgical procedures ≤ 7days. No waiting period required following port-a-cath or other central venousaccess placement. Subjects must have complete wound healing from major surgery orminor surgery before first dose of study treatment. Subjects with clinicallyrelevant ongoing complications from prior surgery are not eligible.

• Currently receiving an investigational drug in a clinical trial or participating inany other type of medical research judged not to be scientifically or medicallycompatible with this study. If a patient is currently enrolled in a clinical trialinvolving non-approved use of a therapeutic device for cancer control, thenagreement with the investigator and the sponsor (MD Anderson IND Office) is requiredto establish eligibility.

• Has received a live vaccine within 30 days prior to the first dose of study drug.Examples of live vaccines include, but are not limited to, the following: BacilleCalmette-Guérin vaccine, measles, mumps, rabies, rubella, typhoid vaccine,varicella/zoster, and yellow fever. Seasonal influenza vaccines for injection aregenerally killed virus vaccines and are allowed; however, intranasal influenzavaccines are live attenuated vaccines and are not allowed. COVID19 vaccinesincluding killed virus are allowed.

• Caution should be exercised when administering nab-paclitaxel concomitantly withknown substrates or inhibitors of CYP2C8 and CYP3A4 (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers).

• Symptomatic primary tumors or metastasis in the brain and/or central nervous systemthat are uncontrolled with antiepileptics and/or require steroids at a dose ofprednisone > 10 mg/day or equivalent.

• Evidence of leptomeningeal or lymphangitic carcinomatosis.

• A history of another primary malignancy that is currently clinically significant,requiring active intervention except for hormone therapy.

• Lactation or pregnancy.

• Human immunodeficiency virus requiring HAART treatment due to unknown drug-druginteractions or has known active hepatitis B (e.g., HBsAg reactive) or C virus (e.g., HCV RNA [quantitative] is detected) infection: patients who have had activeHBV or HCV infections in the past but have evidence of viral clearance as shown bynegative viral load, i.e., undetectable HBV DNA or HCV RNA, will be eligible.

• Concurrent immunosuppressive therapy or steroid (> 10 mg/day prednisone orequivalent).

• History of autoimmune disease including but not limited to inflammatory boweldisease, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, Wegener'sgranulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis,vasculitis, or glomerulonephritis, which requires systemic therapy in the past 2years.

• Note: Patients with vitiligo, resolved childhood asthma/atopy, hypothyroidismon stable hormone replacement, controlled asthma, Type I diabetes, Graves'disease, or Hashimoto's disease, are not excluded.

• History of grade ≥ 3 immune-related adverse events with previous immunotherapy.Note: Patients with adequately treated skin rash other than Steven-Johnson, toxicepidermal necrolysis of other severe forms of dermatitis; or replacement therapy forendocrinopathies, are not excluded.

• History of interstitial lung disease or (non-infectious) pneumonitis that requiredsteroids or current pneumonitis.

• History of grade ≥ 3 allergic reaction to treatment with a monoclonal antibody.

• Patients with Urinary Outflow Obstruction (apply to cyclophosphamide-based regimensonly).