The purpose of this study is to determine the safety and tolerability of TAK-981 in
combination with rituximab in participants with r/r CD20+ NHL in Phase 1b, and to evaluate
the efficacy of TAK-981 in combination with rituximab in r/r CD20+ NHL in Phase 2.
The drug being tested in this study is called TAK-981 in combination with rituximab. The
study will determine the safety, tolerability and efficacy of TAK-981 in combination with
rituximab in participants with r/r CD20+ NHL. The study will include a dose escalation phase
(Phase 1b) and an open label study (Phase 2).
The study will enroll approximately 90 participants, approximately 34 participants in Phase
1b and approximately 56 participants in Phase 2. The phase 1b will identify the maximum
tolerated dose (MTD) and/or pharmacologically active dose (PAD). In the dose escalation
phase, the starting dose of TAK-981 will be 3 mg, however, a starting dose of TAK-981 that is
greater than (>) 3 mg may be considered if emerging preliminary safety experience from the
ongoing TAK-981-1002 single agent study supports it. The starting dose level will be
escalated based on available safety, PK and pharmacodynamic data, and after any early
antitumor activity is observed.
Participants in the Phase 2b will be enrolled once the Phase 1b of the study is completed,
and MTD and/or PAD is determined. Participants in Phase 2 will be enrolled in 2 treatment
arms: indolent non-Hodgkin lymphoma (iNHL) and aggressive non-Hodgkin lymphoma (aNHL).
This multi-center trial will be conducted in the United States and Canada. The overall time
to participate in this study is approximately 36 months. Participants will make multiple
visits to the clinic, and will attend the end of treatment (EOT) visit 30 days after
receiving their last dose of drug or before the start of subsequent systemic anticancer
therapy, whichever occurs first for a follow-up assessment.
Inclusion Criteria:
Each participant must meet all the following inclusion criteria to be enrolled in the
study:
1. CD20+ aNHL include mantle cell lymphoma (phase 1b only) and diffuse large B-cell
lymphoma (DLBCL) histologies such as transformed DLBCL from low-grade lymphoma
(follicular or others), DLBCL associated with small-cell infiltration in bone marrow,
CD20+ B-cell lymphoma with intermediate features between DLBCL and Burkitt's lymphoma
or with intermediate features between DLBCL and Hodgkin lymphoma, follicular lymphoma
grade 3B, and CD20+ aggressive B-cell lymphoma unclassifiable who must have previously
received rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine,
(Oncovin) and prednisone (R-CHOP) (or equivalent anti-CD20 containing therapy) and 1
additional line of therapy in the r/r setting.
2. CD20+ iNHL (including follicular lymphoma of grades 1-3A and marginal zone lymphoma)
refractory to rituximab or to any other anti-CD20 monoclonal antibodies, who have
received at least 1 prior systemic therapy for r/r iNHL:
o Rituximab or anti-CD20 refractoriness is defined as failure to respond to, or
progression during, any previous rituximab/anti-CD20-containing regimen (monotherapy
or combined with chemotherapy), or progression within 6 months of the last rituximab
or anti-CD20 dose.
- The minimum qualifying rituximab/anti-CD20 dose is 1 full cycle (that is,
weekly*4 doses monotherapy or 1 complete dose if combined with chemotherapy).
- Prior anti-CD20 antibody or cytotoxic drugs may have been administered as single
agents or as components of combination therapies. Each repeated course of the
same single-agent or combination is considered an independent regimen.
3. Must be ineligible or refused autologous or allogenic hematopoietic stem cell
transplantation or Chimeric Antigen Receptor (CAR) T-cell therapy.
4. Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to
(<=) 2.
5. Adequate bone marrow function per local laboratory reference range at screening as
follows:
o Platelet count >=75.0*10^9/L, Grade 2 thrombocytopenia (platelet count >=50.0*10^9
per liter [/L]) is allowed if it is clearly due to marrow involvement with no evidence
of myelodysplastic syndrome or hypoplastic bone marrow if found. Absolute neutrophil
count (ANC) >=1.0*10^9/L. Hemoglobin >=85 gram per liter (g/L) (red blood cell [RBC]
transfusion allowed >=14 days before assessment).
6. Adequate renal and hepatic function, per local laboratory reference range at screening
as follows:
- Calculated creatinine clearance >=45 milliliter per minute (mL/min) using
measured 24-hour creatinine clearance or calculated with modified Cockcroft-Gault
formula. Participants can be enrolled based only on calculated glomerular
filtration rate; however, if creatinine clearance is measured, this value must be
used for inclusion.
- Aspartate aminotransferase and alanine aminotransferase <=3.0*the upper limit of
normal (ULN) of the institution's normal range; bilirubin <=1.5*ULN. Participants
with Gilbert's syndrome may have a bilirubin level >1.5*ULN, per discussion
between the investigator and the medical monitor.
7. Left ventricular ejection fraction (LVEF) >=40 percent (%); as measured by ECG or
multiple gated acquisition scan (MUGA).
8. Suitable venous access for safe drug administration and the study-required PK and
pharmacodynamic sampling.
9. Have at least 1 bidimensionally measurable lesion per Lugano Classification (>1.5
centimeter [cm] in its largest dimension) by computed tomography (CT) that has not
been previously irradiated. In the phase 2 portion of the study >1 measurable lesions
are required, 1 for biopsy, and 1 for response.
10. Willing to consent to 1 mandatory pretreatment and 1 on-treatment skin biopsy during
phase 1b and 1 mandatory pretreatment and 1 on-treatment skin and tumor biopsies
during phase 2. The skin biopsy entry requirement may be discontinued by the sponsor
once there is enough pharmacodynamic evidence of target engagement.
11. Recovered to Grade 1, baseline or established as sequela, from all toxic effects of
previous therapy (except alopecia, neuropathy, autoimmune endocrinopathies with stable
endocrine replacement therapy, neurotoxicity [Grade 1 or 2 permitted], or bone marrow
parameters [any of Grade 1, 2, permitted if directly related to bone marrow
involvement]).
Exclusion Criteria:
Participants meeting any of the following exclusion criteria are not to be enrolled in the
study:
1. CNS lymphoma; active brain or leptomeningeal metastases, as indicated by positive
cytology from lumbar puncture or CT scan/magnetic resonance imaging (MRI).
2. History of Grade >=3 infusion-related reaction (IRR) that lead to permanent
discontinuation of previous rituximab treatment.
3. Posttransplantation lymphoproliferative disease except relapsed NHL after autologous
stem cell transplantation.
4. Prior allogeneic hematopoietic stem-cell transplantation.
5. Lymphomas with leukemic expression.
6. Prior anticancer therapy including chemotherapy, hormonal therapy, or investigational
agents within 2 weeks or within at least 5 half-lives before TAK-981 dosing (up to a
maximum of 4 weeks), whichever is shorter. Low dose steroids (oral prednisone or
equivalent <=20 mg per day), hormonal therapy for prostate cancer or breast cancer (in
adjuvant situation), and treatment with bisphosphonates and receptor activator of
nuclear factor kappa-B ligand (RANKL) inhibitors are allowed.
7. Major surgery within 14 days before the first dose of study drug and not recovered
fully from any complications from surgery.
8. Significant medical diseases or conditions, as assessed by the Investigators and
Sponsor that would substantially increase the risk-benefit ratio of participating in
the study. This includes but is not limited to acute myocardial infarction or unstable
angina within the last 6 months, uncontrolled diabetes mellitus, significant active
bacterial, viral or fungal infections, severely immunocompromised state, severe
non-compensated hypertension and congestive heart failure New York Heart Association
Class III or IV, ongoing symptomatic cardiac arrhythmias of >Grade 2, pulmonary
embolism, or symptomatic cerebrovascular events, or any other serious cardiac
condition (example, pericardial effusion or restrictive cardiomyopathy). Chronic
atrial fibrillation on stable anticoagulant therapy is allowed.
9. Known chronic hepatitis C and/or positive serology (unless due to vaccination or
passive immunization due to immunoglobulin (Ig) therapy) for chronic hepatitis B.
Known Human Immunodeficiency Virus (HIV) infection.
10. Second malignancy within the previous 3 years, except treated basal cell or localized
squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ,
resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for
which the participant is not on active anticancer therapy.
11. Receipt of any live vaccine (example, varicella, pneumococcus) within 4 weeks of
initiation of study treatment.
12. Active, uncontrolled autoimmune disease requiring >20 mg of prednisone or equivalent,
cytotoxics or biologicals.
13. Corticosteroid use within 1 week before the first dose of study drug, except as
indicated for other medical conditions such as inhaled steroid for asthma, topical
steroid use, or as premedication for administration of study drug or contrast.
Participants requiring steroids at daily doses >20 mg prednisone equivalent systemic
exposure daily, or those who are administered steroids for lymphoma control or white
blood cell count lowering are not eligible.
14. Participants with baseline prolongation of the Fridericia-corrected QT interval
(example, repeated demonstration of QTc interval >480 millisecond (ms), history of
congenital long QT syndrome, or torsades de pointes).
15. Receiving or requiring the continued use of medications that are known to be strong or
moderate inhibitors and inducers of Cytochrome P450 3A4/5b (CYP3A4/5 b) and strong
P-glycoprotein (Pgp) inhibitors. To participate in this study, such participants
should discontinue use of such agents for at least 2 weeks (1 week washout for
CYP3A4/5 inhibitors, and 2 weeks washout if using CYP3A4/5 inducers) before receiving
a dose of TAK-981.
