Ensayos clínicos

Inclusion Criteria: 

Part 1 Dose Escalation:

• Histological or cytological diagnosis of solid tumor or Hodgkin’s Lymphoma who have relapsed or progressed and who are ineligible for all therapies with demonstrated clinical benefit.
  • Note: there is no limit to the number of prior treatment regimens; or
• Relapsed/refractory CD20 positive, B-cell NHL who have progressed following at least 2 prior systemic therapies. For aggressive histologies, frontline treatment must have included an alkylating agent; or
• Relapsed/refractory classical Hodgkin’s Lymphoma who have progressed following at least 2 prior systemic therapies and have progressed on checkpoint inhibitors (for Part 1B only);
• In Part 1A (45 mg/kg dose cohort only), Part 1B or Part 1C, archival tumor tissue and fresh post-treatment tumor biopsy obtained that allows preparation of the number of slides required in the separate study-specific specimen preparation instructions. Samples will be collected, processed and stored according to a separate laboratory manual.

Part 2 Dose Expansion for Combination Therapy with Rituximab:

• Relapsed/refractory DLBCL including histologically confirmed de novo (NOS) or transformed DLBCL (including transformation from follicular lymphoma of any grade, gastric MALT lymphoma and non-gastric MALT lymphoma) expressing CD20 by IHC (immunohistochemistry) or flow cytometry, primary mediastinal large B‐cell lymphoma, or T‐cell rich large B cell lymphoma, which are relapsed after at least 2 prior lines of systemic therapy including at least one rituximab-containing regimen or refractory disease to rituximab without better available choices.
• Confirmed marginal zone or follicular lymphoma (Grade 1-3a) expressing CD20+ by IHC or flow cytometry, relapsed after at least 2 prior line of systemic therapy including at least one rituximab-chemotherapy combination regimen or refractory to rituximab-containing regimen without better available choices; for indolent NHL histology, progression following prior treatment with an alkylating agent is allowed but not required.
  • NOTE: Refractory disease is defined as progression within 6 months of last dose of therapy. Relapsed disease is defined as disease recurrence or PD following a response after more than 6 months after last dose. Patients who received CAR-T therapy are allowed but cannot have progressive disease within 3 months of CAR-T therapy.
  • At least one measurable lesion as defined by Lugano criteria (version 2014).
  • Available fresh metastatic biopsy sample prior to study entry and one mandatory on-treatment tumor biopsy in US clinical sites, unless there is difficulty obtaining the sample (e.g., hard to reach tumors or biopsies requiring surgical intervention). Waiver of biopsy samples must be discussed with the medical monitor. Tumor biopsy samples collected should allow for sample preparation as detailed in the separate study-specific specimen preparation instructions. Mandatory archival pre-treatment or optional ontreatment FFPE tumor tissue that allow for sample preparation as detailed in the separate study-specific specimen preparation instructions will be collected from subjects enrolled at sites in China in the NHL cohort of Part 2.

Part 2 Dose Expansion for Combination Therapy with Pembrolizumab:

• Locally advanced or metastatic NSCLC that expresses PD-L1 (Tumor Proportion Score (TPS) ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum containing chemotherapy and checkpoint therapy.
• Patients with NSCLC must have progressed on treatment with one prior PD1/L1 inhibitor administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies.
• Patients who have had more than 1 prior PD-(L)1 inhibitor may be considered after discussion with the Medical Monitor. PD-1/L1 inhibitor treatment progression is defined by meeting all of the following criteria:
  • has received at least 2 doses of the PD-1/L1 inhibitor (must be an approved PD-1/L1 inhibitor);
  • has been on a continuous regimen of the PD-1/L1 inhibitor for at least 4 months without disease progression;
  • has demonstrated radiographic disease progression after PD-1/L1.
• Epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer with any high-grade serous component and immune-oncology (IO) treatment naive subjects with metastases progressed on or after platinum-containing therapy and are not eligible for further platinum-containing treatment. Patients must meet the following criteria:
  • platinum-refractory, platinum-resistant disease defined by progression of disease on a platinum-containing regimen or recurrence of disease within 180 days of receiving the last dose of platinum-based treatment;
  • must not have progressed during the first 3 months of first line platinum-based therapy or must not have progressed within 3 months after completing first line platinum-based therapy;
  • must not have evidence of bowel obstruction requiring hospitalization and decompression within the past 30 days;
  • must not have ascites that requires therapeutic paracentesis in the last 30 days;
  • must not have tumors with low malignant potential (ie. borderline tumors) or mucinous tumors.
  • Prior lines of therapy to include:
    • Patients must have had 1 to 3 prior lines of therapy including at least one bevacizumab-containing regimen or ineligible for all other available therapies; Or
    • Patients must be in the 4th or 5th line of treatment, irrespective of bevacizumab or who are ineligible for all therapies with demonstrated clinical benefit; Or
    • Patients with known BRCA-positive associated cancer or mutation, prior therapy must include PARP inhibitors (unless contraindicated)
  • At least one measurable lesion as defined by RECIST 1.1 solid tumors.
  • Available fresh metastatic biopsy sample prior to study entry and one mandatory on-treatment tumor biopsy, unless there is difficulty obtaining the sample (e.g., hard to reach tumors or biopsies requiring surgical intervention). Waiver of biopsy samples must be discussed with the medical monitor. Tumor biopsy samples collected should allow for sample preparation as detailed in the separate study-specific specimen preparation instructions.

All Subjects:

• Males or females, of any race, age ≥ 18 years;
• Be willing and able to provide written informed consent for the trial.
• Eastern Cooperative Oncology Group Performance Status 0 or 1.
• Subjects able to follow the requirements of the study protocol and complete the trial.
• Women of childbearing potential must:
  • Agree to use at least 2 effective contraceptive methods (1 highly effective method in combination with a barrier method; oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner), one of which must be barrier, from signing the ICF, throughout the study, and for up to 8 weeks following the last dose of TJ011133;
  • If using treatment with rituximab, women of childbearing potential should continue to use effective contraceptive methods for 12 months following treatment with rituximab;
  • If using treatment with pembrolizumab, women of childbearing potential should continue to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment;
  • Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at Screening; and have a negative serum or urine pregnancy test (Investigator’s discretion) within 72 hours prior to Cycle 1 Day -1 of study treatment (note that the screening serum pregnancy test can be used as the test prior to Day -1 study treatment if it is performed within the prior 72 hours);
  • Avoid conceiving for 8 weeks after the last dose of TJ011133;
  • Avoid donation of ova from signing the ICF until 8 weeks after the last dose of TJ011133 (12 months after the last dose of rituximab);
  • Agree to ongoing urine pregnancy testing, if clinically indicated, during the course of the study.
• Males must agree to use a condom (a latex condom is recommended) during sexual contact with a pregnant female or a female of childbearing potential and will avoid donation of sperm or having a female partner conceive from the time of signing the ICF, while participating in the study, during dose interruptions, and for at least 90 days after the last dose of study treatment, even if he has undergone a successful vasectomy.
• Subject with a QT interval corrected for heart rate using Fridericia's formula (QTcF) and/or QT interval corrected for heart rate using Bazett's formula of ≤ 450 msec for males, ≤ 470 msec for females.
• No systemic anti-cancer therapy within 4 weeks of starting study treatment or at least 5 half-lives (whichever is shorter) before study drug administration, and all AEs have either resolved or stabilized.
  • Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• A 28-day washout period after the completion of programmed death-1 (PD-1)/PD-L1 therapy.
• Adequate bone marrow function in subjects with solid tumors, including the following:
  • Part 1
  • Absolute neutrophil count ≥ 1500/μL (≥ 1.5 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 100 × 10^3μL (≥ 100 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration;
  • Part 2
  • Absolute neutrophil count ≥ 1500/μL (≥ 1.5 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 75 × 10^3μL (≥ 75 × 109 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 8 g/dL without transfusion within 2 weeks of the first study drug administration.
  • Adequate bone marrow function in subjects with NHL, including:
  • Part 1
  • Absolute neutrophil count ≥1000/μL (≥ 1.0 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 100 × 10^3μL (≥ 100 × 10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration;
  • Part 2
  • Absolute neutrophil count ≥1000/μL (≥ 1.0 × 10^9 /L) without growth factor support for 7 days (14 days if on pegfilgrastim);
  • Platelet ≥ 50 × 10^3μL (≥ 50 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration. For sites in China, Platelet ≥ 75 × 10^3μL (≥ 50 ×10^9 /L) without transfusion within 2 weeks of the first study drug administration;
  • Hemoglobin ≥ 8 g/dL without transfusion within 2 weeks of the first study drug administration. For sites in China, Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks of the first study drug administration.
• Adequate renal function and serum creatine ≤ 1.5 × ULN or estimated serum creatinine clearance of ≥60 mL/min using the Cockcroft-Gault equation.
• Adequate liver function, including:
  • Total serum bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN if the subject has documented Gilbert syndrome);
  • AST and ALT ≤ 2.5 × ULN; ≤ 5.0 × ULN (if there is liver tumor present).
• Normal parameters within the following (unless the subject is receiving anticoagulant therapy):
  • Prothrombin Time ≤ 1.5 ULN, or 11 to 15 seconds in the absence of a normal range;
  • Partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 × ULN;
  • International normalized ratio ≤1.5 × ULN.
• Resolved acute effects of any prior therapy to baseline severity or Grade ≤ 1 NCI CTCAE version 5.0 except for AEs not constituting a safety risk by Investigator judgment

Exclusion Criteria:

• Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable; i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Subjects with Burkitt’s lymphoma, lymphoblastic lymphoma, Richter's transformation, primary effusion lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma.
• Subjects with mantle cell lymphoma with blastoid and TP53 alterations (applies to Part 1 only, all types of mantle cell lymphoma are excluded in Part 2).
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
  • Left ventricular ejection fraction 25% of the bone marrow (non-lymphoma subjects only), or any subject who has received prior radiotherapy within 2 weeks of the start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease. For NSCLC subjects, radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment is not allowed (Parts 1B and Part 2 in combination with pembrolizumab only).
• Prior treatment with CD47 or SIRPα inhibitors;
• A woman of childbearing potential who has a positive urine pregnancy test (e.g., within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Pregnant or nursing females or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 8 weeks for TJ011133, 120 days for pembrolizumab and 12 months for rituximab after the last dose of study treatment.
• Has a diagnosis of immunodeficiency (known active human immunodeficiency virus, hepatitis B virus/hepatitis C virus infection) or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
• Blood product transfusions within 14 days of Cycle 1 Day 1.
• Prior autologous stem cell transplant ≤3 months prior to starting TJ011133.
• Prior allogeneic stem cell transplant with either standard or reduced intensity conditioning.
• Has received chimeric antigen receptor (CAR) or chimeric antigen receptor T-cell (CAR-T) therapy within 90 days of starting TJ011133 OR has received prior CAR or CAR-T therapy and progressed within 90 days of infusion.
• Has received any experimental antibodies or 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: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Received any vaccine within 7 days of planned start of study therapy. Exceptions may apply with SARS-CoV-2 (COVID-19) vaccine, I-Mab Biopharma will provide up-to-date guidance based on evolving current practices.
• History of AIHA or autoimmune thrombocytopenia.
• Any bleeding history within 6 months of planned start of study therapy.
• Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep venous thrombosis, or pulmonary embolism.
• Any other significant medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk or that would prevent the subject from complying with the study.
• Second malignancy within the last 3 years (Part 2 dose expansion cohort only) with the exception of cutaneous squamous cell carcinoma or cutaneous basal cell carcinoma or cervical carcinoma in situ.
• Active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD.
• Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening.
• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab or rituximab and/or any of its excipients;
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Not recovered (i.e., to ≤ Grade 1 or to baseline) from AEs emerging from previous treatments (except alopecia or neuropathy).
• Incomplete recovery from AEs and/or major surgery (must be ≤ Grade 1).
• History of a ≥ Grade 3 irAE with prior immunotherapy with the exception of non-clinically significant laboratory abnormalities.
• Unwilling or unable to comply with study procedures (including follow-up procedures).

Eligibility last updated 1/19/22. Questions regarding updates should be directed to the study team contact.