LN-145 in Treating Patients with Relapsed or Refractory Ovarian Cancer, Osteosarcoma, or Other Bone and Soft Tissue Sarcomas
This phase II trial studies how well autologous tumor infiltrating lymphocytes LN-145 (LN-145) works in treating patients with ovarian cancer, osteosarcoma, or other bone and soft tissue sarcomas that do not respond to treatment (refractory) or that has come back (relapsed). LN-145 is made by collecting and growing specialized white blood cells (called T-cells) that are collected from the patient's tumor. The T cells may specifically recognize, target, and kill the tumor cells.
- Age between 18 and 70 (Subjects aged 16-70 may be enrolled into the osteosarcoma cohort).
- Subjects must be willing and able to provide informed consent. For patients < 18 years of age, their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1 at enrollment and within 7 days of initiating lymphodepleting chemotherapy.
- Subjects must have an area of tumor amenable to excisional biopsy (core biopsies may be allowed as detailed in protocol) for the generation of TIL separate from, and in addition to, a target lesion to be used for response assessment.
- Any prior therapy directed at the malignant tumor, including radiation therapy, chemotherapy, and biologic/targeted agents must be discontinued at least 28 days prior to tumor resection for preparing TIL therapy.
- Absolute neutrophil count (ANC) >= 1000/mm^3 (within 7 days of enrollment).
- Hemoglobin >= 9.0 g/dL (transfusion allowed) (within 7 days of enrollment).
- Platelet count >= 100,000/mm^3 (within 7 days of enrollment).
- Alanine aminotransferase (ALT)/ serum glutamate pyruvate transaminase (SGPT) and aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) =< 2.5 x the upper limit of normal (ULN) (patients with liver metastases may have liver function tests [LFT]) =< 5.0 x ULN (within 7 days of enrollment).
- Calculated creatinine clearance (Cockcroft-Gault) >= 50.0 mL/min (within 7 days of enrollment).
- Total bilirubin =< 1.5 x ULN (within 7 days of enrollment).
- Prothrombin time (PT) & activated partial thromboplastin time (aPTT) =< 1.5 x ULN (correction with vitamin K allowed) unless subject is receiving anticoagulant therapy (which should be managed according to institutional norms prior to and after excisional biopsy) (within 7 days of enrollment)
- Negative serum pregnancy test (female subjects of childbearing potential) (within 7 days of enrollment)
- Subjects must not have a confirmed human immunodeficiency virus (HIV) infection.
- Subjects must have a 12-lead electrocardiogram (EKG) showing no active ischemia and Fridericia's corrected QT interval (QTcF) less than 480 ms.
- Subjects 40 years of age and older must also have a negative dobutamine stress.
- Subjects of childbearing potential must be willing to practice an approved highly effective method of birth control starting at the time of informed consent and for 1 year after the completion of the lymphodepletion regimen. Approved methods of birth control are as follows: hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation or hysterectomy; subject/partner status post vasectomy; implantable or injectable contraceptives; and condoms plus spermicide.
- Able to adhere to the study visit schedule and other protocol requirements.
- Pulmonary function tests (spirometry) demonstrating forced expiratory value (FEV) 1 greater than 65% predicted or forced vital capacity (FVC) greater than 65% of predicted.
- Ovarian cancer cohort only: Subjects must have high-grade non-mucinous histology (carcinosarcomas are allowed).
- Ovarian cancer cohort only: Subjects must have platinum refractory or resistant disease.
- Osteosarcoma cohort only: Subjects with osteosarcomas must have relapsed or become refractory to conventional therapy and have received a regimen including some combination of high-dose methotrexate, doxorubicin, cisplatin, and/or ifosfamide.
- Other bone and soft tissue sarcomas cohort only: Subjects with dedifferentiated chondrosarcomas, dedifferentiated giant cell tumor of bone, giant cell tumor of bone, undifferentiated pleomorphic sarcoma of bone, or high-grade unclassified sarcomas of bone must have received at least one prior line of therapy unless no standard first-line therapy exists in which case enrollment as initial therapy is allowed.
- Other bone and soft tissue sarcomas cohort only: Subjects with other soft tissue sarcomas who have received at least one line of therapy.
- Active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system. Principal investigator (PI) or his/her designee shall make the final determination regarding appropriateness of enrollment.
- Patients with active viral hepatitis.
- Patients who have a left ventricular ejection fraction (LVEF) < 45% at screening.
- Patients with a history of prior adoptive cell therapies.
- Persistent prior therapy-related toxicities greater than grade 2 according to Common Toxicity Criteria for Adverse Events (CTCAE) version (v)4.03, except for peripheral neuropathy, alopecia, or vitiligo prior to enrollment.
- Primary immunodeficiency.
- History of organ or hematopoietic stem cell transplant.
- Chronic steroid therapy, however prednisone or its equivalent is allowed at =< 10 mg/day.
- Patients who are pregnant or nursing.
- Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his/her designee, would prevent adequate informed consent.
- History of clinically significant autoimmune disease including active, known, or suspected autoimmune disease. Subjects with resolved side effects from prior checkpoint inhibitor therapy, vitiligo, psoriasis, type 1 diabetes or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded. Subjects with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be excluded.
- History of clinically significant chronic obstructive pulmonary disease (COPD), asthma, or other chronic lung disease.
- History of a second malignancy (diagnosed in the last 5 years). Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
- History of known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to initiation of lymphodepletion.
- Has received a live vaccine within 30 days prior to the initiation of lymphodepletion.
- Patients who have a contraindication to or history of hypersensitivity reaction to any components or excipients of the TIL therapy or the other study drugs: non-myeloablative-lymphodepletion (NMA-LD) (cyclophosphamide, mesna, and fludarabine); IL-2; antibiotics of the aminoglycoside group (i.e., streptomycin, gentamicin); any component of the TIL infusion product formulation including human serum albumin (HSA), IL-2, and dextran-40.
- Any other condition that in the investigator’s judgement would significantly increase the risks of participation.
Locations & Contacts
Contact: Amir Anthony Jazaeri
Trial Objectives and Outline
I. To evaluate efficacy using objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 in each cohort.
I. Determine the disease control rate (DCR) within and across cohorts.
II. Determine the duration of response (DOR).
III. Determine progression-free survival (PFS) and overall survival (OS).
IV. Further characterize the safety profile of adoptive cell therapy with tumor infiltrating lymphocytes (TIL) across multiple tumor types.
I. Establish duration of tumor-infiltrating lymphocyte (TIL) persistence.
II. Compare the molecular and immunological features of tumors before and after TIL therapy.
III. Prospectively evaluate the existing immunotherapy response criteria (immune-related [ir]RECIST) as the best response assessment tool for TIL therapy among a diverse group of solid tumors.
IV. To investigate TIL attributes (CD8 percentage [%], CD27 and CD28 expression) and correlation with response to therapy.
V. Assess tumor marker (CA-125) response in patients who produce this tumor marker.
VI. To assess Health-Related Quality of Life (HRQOL).
Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -7 and -6, fludarabine phosphate IV over 30 minutes daily on days -5 to -1, autologous tumor infiltrating lymphocytes LN-145 IV over 45 minutes on day 0 and aldesleukin IV over 30 minutes on days 1-4 for up to 6 doses.
After completion of study treatment, patients are followed up at 18 weeks, 6, 9, 12, 18 and 24 months, then every 3 months for 3 years.
Trial Phase & Type
M D Anderson Cancer Center
Amir Anthony Jazaeri
Secondary IDs NCI-2018-00918
Clinicaltrials.gov ID NCT03449108