This phase Ib/II trial identifies the best dose and possible benefits and/or side effects of
magrolimab when given in combination with mogamulizumab in treating patients with stage IB-IV
mycosis fungoides or Sezary syndrome types of T-cell lymphoma that has come back (relapsed)
or does not respond to treatment (refractory). Magrolimab and mogamulizumab are monoclonal
antibodies that may interfere with the ability of cancer cells to grow and spread. Treatment
with magrolimab in combination with mogamulizumab may stabilize cancer for longer period than
the usual treatment in patients with relapsed/refractory T-cell lymphoma who have been
previously treated.
PRIMARY OBJECTIVES:
I. To characterize the safety and toxicity profile and to determine a safe recommended phase
2 dose (RP2D) of Hu5F9-G4 (magrolimab) when given in combination with mogamulizumab. (Phase
I) II. To compare the proportion of patients who achieve a partial or complete response
lasting at least 6 months (ORR6) of the combination of Hu5F9-G4 (magrolimab) and
mogamulizumab versus mogamulizumab alone. (Phase II)
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. (Phase I)
II. To compare the efficacy of the combination of Hu5F9-G4 (magrolimab) and mogamulizumab
versus mogamulizumab alone with respect to the following endpoints (Phase II):
IIa. Overall response rate (ORR); overall response rate lasting at least 4 months (ORR4);
overall response rate lasting at least 12 months (ORR12).
IIb. Duration of response (DOR). IIc. Progression-free survival (PFS). IId. Time to next
treatment (TTNT).
EXPLORATORY OBJECTIVES:
I. To identify potential biomarkers that correlate with response to mogamulizumab and
Hu5F9-G4 (magrolimab) including (Phase I and II):
Ia. Expression of CCR4. Ib. Somatic mutations and germline polymorphisms. Ic. Phenotyping of
lymphoma and immune microenvironment. Id. Functional assay of phagocytosis.
OUTLINE: This is a phase Ib, dose de-escalation study of magrolimab followed by a phase II
study. Patients in the phase Ib study receive treatment as in Arm I. Patients in the phase II
study are randomized to Arm I or Arm II.
ARM I: Patients receive magrolimab intravenously (IV) over 2-3 hours weekly during cycles
1-2, then every 2 weeks (Q2W) during cycles 3-12. Patients also receive mogamulizumab IV over
at least 60 minutes weekly during cycle 1, then Q2W during cycles 2-12. Cycles repeat every
28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive mogamulizumab IV over at least 60 minutes weekly during cycle 1,
then Q2W during cycles 2-12. Cycles repeat every 28 days for up to 12 cycles in the absence
of disease progression or unacceptable toxicity. Patients who have received at least 2 full
treatment cycles and have progressive disease (PD) or have received at least 6 full treatment
cycles and have stable disease (SD) may crossover to Arm I.
After completion of study treatment, patients are followed up every 3 months for 2 years.
Inclusion Criteria:
- Diagnosis of either MF or SS by the World Health Organization (WHO) 2016
classification (Swerdlow et al., 2017), stage IB-IV by modified International Society
for Cutaneous Lymphomas (ISCL)/ European Organization of Research and Treatment of
Cancer (EORTC) classification (Olsen et al., 2011), without large cell transformation
(LCT) at the time of screening. Patients with a history of prior LCT are permitted
- Patients must have had at least one prior course of systemic therapy
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Hemoglobin >= 9.5 g/dL and transfusion independence (defined as not requiring more
than 2 units of red blood cell [RBC] transfusions during the 4-week period prior to
screening)
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 75,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) except for subjects
with Gilbert's syndrome or genetic equivalent
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2 by the Cockcroft-Gault formula
- Patients must meet the following minimum wash-out window from previous treatments to
the first treatment
- >= 3 weeks for systemic anti-cancer therapies
- >= 2 weeks for phototherapy, local radiation therapy, topical high potency
corticosteroid, topical retinoid, topical nitrogen mustard, or topical toll-like
receptor (TLR)-agonist
- >= 12 weeks for total skin electron beam therapy Participants with rapidly
progressive malignant disease may be enrolled prior to completion of the above
periods with approval of the protocol director
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression for a
minimum of 3 months
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
- The effects of Hu5F9-G4 (magrolimab) on the developing human fetus are unknown. For
this reason and because monoclonal antibody agents as well as other therapeutic agents
used in this trial (mogamulizumab) are known to be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry and for the duration of study
participation and continue for 4 months after the last dose of both Hu5F9-G4
(magrolimab) and mogamulizumab. Effective contraception is defined as oral
contraceptives, double barrier method (condom plus spermicide or diaphragm plus
spermicide) or practice true abstinence from heterosexual intercourse. Women of
childbearing potential includes any female who has experienced menarche and has not
undergone successful surgical sterilization or is not postmenopausal (defined as
amenorrhea >= 12 consecutive months). Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men treated or enrolled on this protocol who are
sexually active with women of childbearing potential and who have not had vasectomies
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of Hu5F9-G4 (magrolimab)
administration
- Female patients of childbearing potential must not be nursing or planning to be
pregnant and must have a negative urine or serum pregnancy test within 30 days before
randomization and within 72 hours before the first administration of study treatment
- Female patients of childbearing potential must be willing to use one highly
effective method of contraception during the study and continue for 4 months
after the last dose of study treatment
- Male patients who are sexually active with a woman of childbearing potential
(WOCBP) and who have not had vasectomies must be willing to use a barrier method
of contraception (condom plus spermicidal gel) and refrain from sperm donation
during the study and for 4 months after the last dose of study treatment. If the
partner is pregnant, male patients must use barrier method contraception (condom)
during the study and for 4 months after the last dose of study treatment to
prevent fetal exposure to study treatment
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
- Willing to comply with clinic visit schedule and procedures including mandatory
biopsies
Exclusion Criteria:
- Prior treatment with Hu5F9-G4 (magrolimab) or any agent targeting CD47-SIRPalpha
- Prior treatment with mogamulizumab
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia and
lymphopenia (any grade permitted). Residual peripheral neuropathy must have improved
to grade 2 or better
- Patients who are receiving any other investigational agents
- Allogeneic hematopoietic stem cell transplant recipients with any graft-versus-host
disease within the previous 3 months or requiring immunosuppression
- Active autoimmune disease that has required systemic immunosuppressive medication
within the previous 3 months
- Active herpes simplex or herpes zoster. Subjects on prophylaxis for herpes who have no
active signs of active infection, and whose last active infection was more than 6
months ago, may enter the study, and should continue to take the prescribed medication
for the duration of the study
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Hu5F9-G4 (magrolimab), other monoclonal antibodies, or other agents
(mogamulizumab) used in study
- Significant cardiopulmonary disease defined as
- Acute myocardial infarction within the last 6 months
- Unstable angina
- Congestive heart failure New York Heart Association (NYHA) class III-IV
- Patients with uncontrolled intercurrent illness requiring antibiotics. Patients on
prophylactic antibiotics for non-complicated staphylococcus colonization/infection are
eligible
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are excluded
- Patients with psychiatric illness/social situations or substance abuse that would
limit compliance with study requirements
- Pregnant women are excluded from this study because Hu5F9-G4 (magrolimab) is
monoclonal antibody agent with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with Hu5F9-G4 (magrolimab), breastfeeding should
be discontinued if the mother is treated with Hu5F9-G4 (magrolimab). These potential
risks may also apply to other agents used in this study (mogamulizumab)
- Patients with RBC transfusion dependence, defined as requiring more than 2 units of
RBCs transfused during the 4-week period prior to screening. RBC transfusions are
permitted during the screening period and prior to enrollment
- Patients with prior autoimmune thrombocytopenia, hemolytic anemia or Evans syndrome
requiring treatment in the last 12 months
- Patients on the following medications at the time of enrollment:
- Immunotherapy or immunosuppressive drugs (e.g. chemotherapy or systemic
corticosteroids) EXCEPT for the following:
- Intranasal, inhaled, or local steroid injection (e.g. intra-articular
injection)
- Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or
equivalent, if patient has been on a stable dose for at least 2 weeks prior
to the first treatment
- Low and medium potency topical corticosteroids are permitted if patient has
been on a stable dose for at least 2 weeks prior to the first treatment
- Steroids as premedication for hypersensitivity reactions (e.g. computed
tomography [CT] scan premedication)
- Growth factors (granulocyte colony stimulating factor or granulocyte macrophage
colony stimulating factor) EXCEPT for erythropoietin and darbepoetin alpha
- Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or
known to potentially interfere with major organ function (e.g. hypericin)
- Live vaccines are not allowed while participating in the trial. Examples of live
vaccines include, but are not limited to, the following: measles, mumps, rubella,
chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), typhoid (oral)
vaccine, and intranasal influenza vaccines (e.g., Flu-Mist). However, seasonal
influenza vaccines for injection are generally killed virus vaccines and are allowed
