Personalized Neoantigen Cancer Vaccine (NeoVax) plus Pembrolizumab after Front-Line Rituximab for the Treatment of Grade I-IIIa Follicular Lymphoma
This phase I trial evaluates the feasibility of a personalized neoantigen cancer vaccine called NeoVax given in combination with pembrolizumab after rituximab in treating patients with grade I-IIIa follicular lymphoma. NeoVax is made up of small protein fragments, which are called “peptides" and a drug called Poly-ICLC. Poly-ICLC (also called Hiltonol) is an experimental “viral mimic” and an activator of immunity. Poly-ICLC binds proteins on the surface of certain immune cells to make it appear as if a virus is present. When the cells detect the vaccine, they think it is a virus and turn on the immune system. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving NeoVax and pembrolizumab after rituximab may help the immune system recognize and fight follicular lymphoma cells.
Inclusion Criteria
- INCLUSION CRITERIA AT TIME OF SCREENING REGISTRATION
- Diagnosis of grade I-IIIA follicular lymphoma (pathology must be confirmed at Dana-Farber Cancer Institute [DFCI]/Brigham and Women's Hospital [BWH])
- Planned treatment with 4 weekly doses of rituximab
- No prior systemic therapy for follicular lymphoma; prior radiation with palliative or curative intent is allowed if radiation occurred more than 3 months prior to study entry
- Patient must have measurable disease by Cheson criteria
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status < 2
- Hemoglobin > 9 gm/dl (erythropoiesis-stimulating agents [ESAs] or transfusion are not allowed) (greater than 8 gm/dl if there is lymphoma involvement of the bone marrow)
- Absolute neutrophil count (ANC) > 1000 (greater than 750 if there is lymphoma involvement of the bone marrow)
- Platelet count > 100,000 (greater than 50,000 if there is lymphoma involvement of the bone marrow)
- International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) < 1.5 x upper limit of normal (ULN) unless subject is on anticoagulation as long as PT or activated partial thromboplastin time (aPTT) is within intended therapeutic range of anticoagulant used
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal(< 5 x ULN if there are hepatic metastases)
- Creatinine < 1.5 x ULN or measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine clearance) > 30 ml/min for subject with creatinine > 1.5 x institutional ULN
- Total bilirubin less than institutional 1.5 x ULN (or a direct bilirubin < ULN if total bilirubin is > 1.5 x ULN)
- The effects of NeoVax and poly-ICLC on the developing human fetus are unknown. For this reason, women of childbearing potential (WOCBP) must have a negative pregnancy test (serum) before entry onto the trial and within 7 days prior to start of study vaccination
- Female patients enrolled in the study, who are not free from menses for > 2 years, post hysterectomy / oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from sexual activity throughout the study, starting with visit 1 through 4 weeks after the last dose of study therapy. Approved contraceptive methods include for example; intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception. Male participants need to agree to use an adequate method of contraception
- Patient is agreeable to provide baseline and on-treatment tumor samples according to the study protocol. The patient is willing to allow tumor and normal tissue samples to be submitted for complete exome and transcriptome sequencing
- Ability to understand and the willingness to sign a written informed consent document
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: At least 7 immunizing peptides can be designed
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: Continue to meet inclusion and exclusion criteria for screening registration (note: hepatitis B and hepatitis C serologies do not need to be repeated unless there is a clinical concern that an exposure has occurred since the screening phase)
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: Achieved a CR, PR, or SD with no residual mass greater than 5 cm per Lugano criteria following single agent rituximab
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: Hemoglobin > 9 gm/dl (ESAs or transfusion are not allowed) (greater than 8 gm/dl if there is lymphoma involvement of the bone marrow) (within 10 days prior to the start of study treatment)
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: ANC > 1000 (greater than 750 if there is lymphoma involvement of the bone marrow) (within 10 days prior to the start of study treatment)
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: Platelet count > 100,000 (greater than 50,000 if there is lymphoma involvement of the bone marrow) (within 10 days prior to the start of study treatment)
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) < 1.5 x ULN unless subject is on anticoagulation as long as PT or aPTT is within intended therapeutic range of anticoagulant used (within 10 days prior to the start of study treatment)
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal (< 5 x ULN if there are hepatic metastases) (within 10 days prior to the start of study treatment)
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: Creatinine < 1.5 x ULN or measured or calculated creatinine clearance (GFR can also be used in place of creatinine clearance) > 30 ml/min for subject with creatinine > 1.5 x institutional ULN (within 10 days prior to the start of study treatment)
- ADDITIONAL INCLUSION CRITERIA FOR TREATMENT REGISTRATION: Total bilirubin less than institutional 1.5 x ULN (or a direct bilirubin < ULN if total bilirubin is > 1.5 x ULN) (within 10 days prior to the start of study treatment)
Exclusion Criteria
- Recovered from all adverse events (AEs) due to rituximab to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
- Has received prior systemic anti-cancer therapy, including investigational agents, with the exception of 4 weekly doses of rituximab administered per protocol
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137)
- Has received prior radiotherapy within 2 weeks of start of study treatment or radiation with curative intent within 90 days of study enrollment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Patients will be excluded if they received radiation at any time to the only site of measurable disease
- Is currently participating in or has participated in a study of an investigational agent for treatment of a non-malignant condition or has used an investigational device within 4 weeks prior to the first dose of study treatment
- Previous bone marrow or stem cell transplant
- Concomitant therapy with immunosuppressive or immunomodulatory agents; chronic use of systemic corticosteroids at doses of 10 mg of prednisone (or equivalent) for indications other than treatment of follicular lymphoma is acceptable. Use of higher doses of corticosteroids after initial registration is acceptable if tapered to 10 mg of prednisone (or equivalent) or les at least 7 days prior to NeoVax administration so long as the corticosteroids were not administered for follicular lymphoma
- 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: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (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. Vaccination against SARS-CoV-2 virus for the prevention of COVID 19 is allowed in this study.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to poly-ICLC
- Has active autoimmune disease that has required systemic treatment in the 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, etc.) is not considered a form of systemic treatment
- Has an active infection requiring systemic therapy
- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Progressive disease or stable disease with residual tumor mass > 5 cm by computed tomography (CT) scan (measured as long axis) following 4 weekly doses of rituximab (for treatment phase only)
- Any documented transformation to diffuse large B cell lymphoma or grade 3B follicular lymphoma
- Currently requiring chronic intravenous immunoglobulin G (IVIG)
- Has a known history of human immunodeficiency virus (HIV)
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection. Note: no testing for hepatitis B and Hepatitis C is required unless mandated by local health authority
- Has a known history of active TB (Bacillus Tuberculosis)
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
- Pregnant women are excluded from this study because personalized neoantigen peptides and poly-ICLC are agents with unknown risks to the developing fetus. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with personalized neoantigen peptides and poly-ICLC, nursing women are excluded from this study
- Individuals with history of an invasive malignancy are ineligible except for the following circumstances: a) individuals with a history of invasive malignancy are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; b) individuals with the following cancers are eligible if diagnosed and treated: carcinoma in situ of the breast, oral cavity or cervix and basal cell or squamous cell carcinoma of the skin; c) individuals with prostate cancer managed with active surveillance that is not expected to limit their survival to < 10 years
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03361852.
PRIMARY OBJECTIVE:
I. To evaluate the feasibility of NeoVax + T helper peptide in combination with pembrolizumab following 4 weekly doses of rituximab in subjects with previously untreated grade 1-3A follicular lymphoma.
II. To compare the frequency of neoantigen-specific CD8+ T cell responses among patients who receive Neovax alone compared to Neovax plus pembrolizumab.
SECONDARY OBJECTIVES:
I. To assess the induction of neoantigen-specific cellular immune responses following administration of NeoVax + T helper peptide with or without pembrolizumab.
II. To assess the proportion of patients who convert from partial response (PR) to complete response (CR) or from stable disease (SD) to PR/CR as best objective response following NeoVax with or without pembrolizumab.
III. To assess the safety and toxicity of NeoVax in with or without pembrolizumab following 4 weekly doses of rituximab in patients with previously untreated follicular lymphoma.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT A: Patients receive standard of care rituximab once weekly (QW) for up to 4 doses in the absence of disease progression or unacceptable toxicity. Within 8-12 weeks after completion of rituximab treatment, patients are restaged. Patients with at least 7 neoantigens identified then receive NeoVax intradermally (ID) and subcutaneously (SC) into up to 4 different anatomic sites on days 1, 4, 8, 15, 22, 78, and 134 in the absence of disease progression or unacceptable toxicity. Patients also receive neoantigen peptides ID on day 85 in either forearm. Additionally, patients undergo tumor biopsy, bone marrow biopsy and aspiration and blood sample collection on study and computed tomography (CT) or positron emission tomography (PET)/CT throughout the study.
COHORT B: Patients receive rituximab, NeoVax, and neoantigen peptides as in Cohort A. Starting week 12 (on day 78), patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo tumor biopsy, bone marrow biopsy and aspiration and blood sample collection on study and CT or PET/CT throughout the study.
After completion of study treatment, patients are followed up every 3 months for 3 years, then every 6 months for up to 10 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorReid Merryman
- Primary ID17-353
- Secondary IDsNCI-2020-10068
- ClinicalTrials.gov IDNCT03361852