This study is in 2 parts.
The main aims of the 1st part of the study are to check if people with advanced solid tumors
or cancers in the immune system (lymphomas) have side effects from TAK-981, and to check how
much TAK-981 they can receive without getting side effects from it.
The main aims of the 2nd part of the study are to learn if the condition of people with
specific cancers improves after treatment with TAK-981. Another aim is to check for side
effects from TAK-981.
In the 1st part of the study, participants will receive TAK-981. In the 2nd part of the
study, participants with specific tumor types will receive TAK-981 at the recommended phase 2
dose determined during the 1st part of the study.
In both parts of the study, participants can receive TAK-981 for up to 1 year or longer if
their condition stays improved.
The drug being tested in this study is called TAK-981. TAK-981 is being tested to evaluate
safety, tolerability, preliminary efficacy and PK in participants with advanced or metastatic
solid tumors or relapsed/refractory hematologic malignancies. The study will include 2
phases: Phase 1 dose escalation and Phase 2 dose expansion cohorts (cancer treatment
expansions).
The study will enroll approximately 202 participants, approximately 70 participants in the
dose escalation phase, approximately 132 participants in cancer treatment expansion phase.
In the dose escalation, dose levels will be escalated based on safety, and available PK and
pharmacodynamic data and will also determine the single agent RP2D. Participants in dose
expansion phase will be enrolled, once RP2D is determined. There will be 6 cohorts in cancer
treatment expansions as following:
- Cohort A: Nonsquamous NSCLC
- Cohort B: Cervical cancer
- Cohort C: MSS-CRC
- Cohort D: Relapsed/refractory DLBCL progressed or relapsed after CAR T-cells therapy
- Cohort E: Relapsed/refractory DLBCL that have not received prior cellular therapy
- Cohort F: Relapsed/refractory FL
This multi-center trial will be conducted in the United States and Canada. The overall time
to participate in this study is approximately 4 years. The overall time to receive treatment
in the dose escalation and cancer treatment is approximately 1 year. Based on decision of
sponsor, participants with demonstrated clinical benefit can continue treatment beyond 1
year. Participants will make multiple visits to the clinic, and will make a final visit 30
days after receiving their last dose of drug or before the start of subsequent anticancer
therapy, whichever occurs first for a follow-up assessment.
Inclusion Criteria:
1. Adult male or female participants >=18 years old.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Population for Phase 1 dose escalation:
- Has histologically or cytologically confirmed advanced (local regionally
recurrent not amenable to curative therapy) or metastatic solid tumors who have
no standard therapeutic option with a proven clinical benefit, are intolerant, or
have refused them. OR
- Has relapsed/refractory lymphoma not amenable to therapies with proven clinical
benefit or who are intolerant or who refuse them. Participants with low-grade
lymphomas such as FL, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma,
and marginal zone lymphomas, may not need to exhaust all available therapy. These
participants can be enrolled after failure of at least 2 prior systemic
therapies, provided that there is not an immediate need for cytoreduction. In
these cases, participants who need immediate therapy for tumor bulk are not
eligible for this trial.
4. Population for Phase 2 dose expansion cohorts:
o Has histologically or cytologically documented, advanced (metastatic and/or
unresectable) cancer as listed below, that is incurable and for which prior standard
first-line treatment has failed: Note: Prior neoadjuvant or adjuvant therapy included
in initial treatment may not be considered first- or later-line SOC treatment unless
such treatments were completed less than 12 months before the current tumor
recurrence.
o Nonsquamous NSCLC that has progressed to 1 prior systemic immune checkpoint
inhibitors (CPI)/anti-PD-(1/L1)-containing therapy and no more than 2 lines of
therapy. Participants must have not shown evidence of tumor progression during the
first 5 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy
(cohort A).
Note: Participants with known driver mutations/genomic aberrations (example- epidermal
growth factor receptor [EGFR], B-Raf proto-oncogene mutation V600E [BRAF V600E], and
ROS proto-oncogene 1 [ROS1] sensitizing mutations, neurotrophic receptor tyrosine
kinase [NRTK] gene fusions, and anaplastic lymphoma kinase [ALK] rearrangements) must
have also shown progressive disease after treatment with a commercially available
targeted therapy.
o CPI-naïve cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or
adenocarcinoma of the cervix) participants who have received no more than 1 prior
systemic line of therapy for recurrent or Stage IVB cervical cancer (cohort B).
Note: The following cervical tumors are not eligible: minimal deviation/adenoma
malignum, gastric-type adenocarcinoma, clear-cell carcinoma, and mesonephric
carcinoma. Histologic confirmation of the original primary tumor is required via
pathology report.
Note: First-line treatment must have consisted of platinum-containing doublet.
Chemotherapy administered concurrently with primary radiation (example- weekly
cisplatin) is not counted as a systemic chemotherapy regimen.
o CPI-naïve MSS-CRC participants who have progressed on no more than 3 chemotherapy
regimens (cohort C).
Note: Participants must have received prior treatment with fluoropyrimidine-,
oxaliplatin-, and irinotecan-containing regimens if indicated.
- Relapsed/refractory DLBCL progressed or relapsed after prior CAR T cell therapy
that has received approval by a health authority for the treatment of DLBCL
(cohort D).
- Relapsed/refractory DLBCL that has progressed or relapsed after at least 2 but no
more than 3 prior lines of systemic therapy and has not received prior cellular
therapy. At least one prior line of therapy must have included a CD20-targeted
therapy (cohort E).
- Relapsed/refractory FL that has progressed or relapsed after at least 2 but no
more than 3 prior lines of systemic therapy. At least 1 prior line of therapy
must have included a CD20-targeted therapy (cohort F).
5. In Phase 2 only, have at least 1 radiologically measurable lesion based on RECIST v1.1
for participants with solid tumors or Lugano criteria for lymphoma. Tumor lesions
situated in a previously irradiated area are considered measurable if progression has
been demonstrated in such lesions.
Note: In Phase 2 stage 1, have an additional lesion for pretreatment and on-treatment
biopsy.
6. In Phase 2 stage 1, willing to consent to mandatory pretreatment and on-treatment
tumor biopsy.
Note: For fresh tumor biopsies, the lesion must be accessible for a biopsy procedure
as assessed by the investigator.
7. Is willing to provide archival tumor tissue sample, if available.
8. Adequate bone marrow reserve and renal and hepatic function.
9. Recovered to Grade 1 or baseline or established as sequelae from all toxic effects of
previous therapy (except alopecia, neuropathy, or autoimmune endocrinopathies with
stable endocrine replacement therapy, bone marrow parameters [any of Grade 1 or 2
permitted if directly related to bone marrow involvement).
10. Consented to undergo serial skin punch biopsies (dose escalation only).
11. Suitable venous access for safe drug administration and the study-required PK and
pharmacodynamics sampling.
12. Women of childbearing potential participating in this study should avoid becoming
pregnant, and male participants should avoid impregnating a female partner.
Nonsterilized female participants of reproductive age and male participants should use
effective methods of contraception through defined periods during and after study
treatment as specified below. Female participants must meet 1 of the following:
- Postmenopausal for at least 1 year before the screening visit, or
- Surgically sterile, or
- If they are of childbearing potential, agree to practice 1 highly effective
method and 1 additional effective (barrier) method of contraception at the same
time, from the time of signing of the informed consent form (ICF) through 120
days after the last dose of study drug (whichever is longer), or
- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the participant. (Periodic abstinence [example, calendar,
ovulation, symptothermal, postovulation methods], withdrawal, spermicides only,
and lactational amenorrhea are not acceptable methods of contraception. Female
and male condoms should not be used together.)
13. Male participants, even if surgically sterilized (that is, status postvasectomy) must
agree to 1 of the following:
- Agree to practice effective barrier contraception during the entire study
treatment period and through 120 days after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the participant. (Periodic abstinence [example, calendar,
ovulation, symptothermal, postovulation methods], withdrawal, spermicides only,
and lactational amenorrhea are not acceptable methods of contraception. Female
and male condoms should not be used together.)
Exclusion Criteria:
1. Phase 1 dose escalation and Phase 2 cancer treatment expansion cohorts:
o Has received treatment with systemic anticancer treatments or investigational
products within 14 days before the first dose of study drug or 5 half-lives, whichever
is shorter.
Note: Low-dose steroids (oral prednisone or equivalent <=20 mg per day), hormonal
therapy for prostate cancer or breast cancer (as adjuvant treatment), and treatment
with bisphosphonates and receptor activator of nuclear factor kappa-Β ligand (RANKL)
inhibitors are allowed.
o Has received extended field radiotherapy <=4 weeks before the start of treatment
(<=2 weeks for limited field radiation for palliation), and who has not recovered to
grade 1 or baseline from related side effects of such therapy (except for alopecia).
2. History of any of the following <=6 months before first dose: congestive heart failure
New York Heart Association Grade III or IV, unstable angina, myocardial infarction,
unstable symptomatic ischemic heart disease, severe noncompensated hypertension
despite appropriate medical therapy, 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.
3. Baseline prolongation of the QT interval with Fridericia correction method (QTcF)
(example, repeated demonstration of QTcF interval >480 milliseconds (ms), history of
congenital long QT syndrome, or torsades de pointes).
4. Psychiatric illness/social circumstances that would limit compliance with study
requirements and substantially increase the risk of adverse events (AEs) or has
compromised ability to provide written informed consent.
5. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
6. History of autoimmune disease requiring systemic immunosuppressive therapy.
7. History of immune-related AEs related to treatment with immune checkpoint inhibitors
that required treatment discontinuation.
8. History of noninfectious pneumonitis that required steroids or a history of
interstitial lung disease.
9. Has evidence of active, noninfectious pneumonitis.
10. Have a significant active infection.
11. Known history of human immunodeficiency virus (HIV) infection or any other relevant
congenital or acquired immunodeficiency.
12. Known hepatitis B virus (HBV) surface antigen seropositive or detectable hepatitis C
infection viral load. Note: Participants who have positive hepatitis B core antibody
or hepatitis B surface antigen antibody can be enrolled but must have an undetectable
hepatitis B viral load.
13. Receiving or requiring the continued use of medications that are known to be strong or
moderate inhibitors and inducers of cytochrome P-450 3A4/5 (CYP3A4/5) or are strong
permeability glycoprotein (P-gp) inhibitors. To participate in this study, such
participants should discontinue use of such agents for at least 2 weeks before
receiving a dose of TAK-981.
14. Participant requires the use of drugs known to prolong QTc interval (during Phase 1
only).
15. History of allogeneic tissue or solid organ transplant.
16. 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.
17. Female participants who are lactating and breastfeeding or have a positive serum
pregnancy test during the screening period or a positive urine pregnancy test on Day 1
before first dose of study drug.
