The purpose of this study is to determine the safety and tolerability of TAK-981 in
combination with pembrolizumab in participants with select solid tumor indications and to
establish the recommended phase 2 dose (RP2D) during Phase 1b of study and to evaluate the
preliminary efficacy of TAK-981 at the RP2D in combination with pembrolizumab in participants
with select solid tumor indications in Phase 2 of the study.
The drug being tested in this study is called TAK-981. TAK-981 is being tested to treat
people who have select advanced or metastatic solid tumors. The study will include a dose
escalation phase and a dose expansion phase.
The study will enroll approximately 101 patients, approximately 32 participants in the dose
escalation phase and approximately 9 to 23 participants in each of the 3 cohorts of dose
expansion phase. Participants will receive escalating doses of TAK-981 and fixed dose of
pembrolizumab until RP2D is determined:
• Dose Escalation: TAK-981 + Pembrolizumab (fixed dose)
Once RP2D is determined, participants of select advanced or metastatic solid tumors will
receive TAK-981 in below defined cohorts in the expansion phase:
- Expansion Phase: Non-squamous NSCLC
- Expansion Phase: Cervical Cancer
- Expansion Phase: Microsatellite Stable Colorectal Cancer (MSS-CRC)
This multi-center trial will be conducted worldwide. The overall time to participate in this
study is 48 months. Participants will make multiple visits to the clinic, and
progression-free survival follow-up for maximum up to 12 months after last dose of study
1. Has a 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 standard of care
treatment unless such treatments were completed less than 12 months prior to the
current tumor recurrence.
A. Non-squamous non-small cell lung cancer (NSCLC) that has progressed to no more than
1 prior systemic immune checkpoint inhibitor (CPI)/anti- programmed cell death protein
1/ligand (PD-1/L1)-containing therapy. In phase 2, non-squamous NSCLC 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.
Note: Participants with known driver mutations/genomic aberrations (e.g. 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
B. CPI-naive 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. 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 (e.g., weekly cisplatin)
is not counted as a systemic chemotherapy regimen.
C. CPI-naïve microsatellite stable-colorectal cancer (MSS-CRC) participants who have
progressed on no more than 3 chemotherapy regimens.
Note: Participants must have received prior treatment with fluoropyrimidine-,
oxaliplatin-, and irinotecan-containing regimens if indicated.
2. Has at least 1 radiologically measurable lesion based on RECIST, Version 1.1. Tumor
lesions situated in a previously irradiated area are considered measurable if
progression has been demonstrated in such lesions.
3. Has a performance status of 0 or 1 on the Eastern Cooperative Group (ECOG) Performance
4. Has left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram
(ECHO) or multiple-gated acquisition (MUGA) scan.
5. Has recovered to Grade 1 or baseline from all toxicity associated with previous
therapy or have the toxicity established as sequela. Note: Has a neuropathy ≤Grade 2,
any grade alopecia, or autoimmune endocrinopathies with stable replacement therapy are
6. Demonstrate adequate organ function as described below:
A. Platelet count ≥75.0 × 10^9/L. B. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L. C.
Hemoglobin ≥85 g/L (red blood cell [RBC] transfusion allowed ≥14 days before assessment).
D. Estimated creatinine clearance using the Cockcroft-Gault formula ≥45 mL/minute for
participants with serum creatinine concentrations above the upper limit of normal (ULN).
E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) ≤3.0 ×
ULN; 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.
1. Has received extended field radiotherapy ≤4 weeks before the start of treatment (≤7
days for limited field radiation for palliation outside the chest or brain).
2. Has a history of uncontrolled brain metastasis (evidence of progression by imaging
over a period of 4 weeks and/or neurologic symptoms that have not returned to
baseline). Participant with treated brain metastases are allowed provided they are
radiologically stable, without evidence of progression for at least 4 weeks by repeat
imaging, clinically stable, and without requirement of steroid treatment for at least
14 days prior to first dose of study treatment. Note: For asymptomatic participants,
screening brain imaging is not required.
3. 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.
4. Major surgery ≤14 days from the first dose of study drug and not recovered fully from
any complications from surgery.
5. Has a history of immune-related adverse events (AEs) related to treatment with immune
CPIs that required treatment discontinuation.
6. Is receiving or requires the continued use of medications that are known to be strong
or moderate inhibitors and inducers of cytochrome P-450 (CYP) 3A4/5. To participate in
this study, such participant should discontinue use of such agents for at least 2
weeks (1 week for CYP3A4/5 inhibitors) before receiving a dose of TAK-981.
7. Had received any live vaccine (e.g., varicella, pneumococcus) within 4 weeks of
initiation of study treatment.
8. Baseline prolongation of the QT interval corrected using Fridericia's formula (QTcF)
(eg, repeated demonstration of QTcF interval >480 ms, history of congenital long QT
syndrome, or torsades de pointes).
9. Has a history of autoimmune disease requiring systemic immunosuppressive therapy with
daily doses of prednisone >10 mg/day or equivalent doses, or any other form of
immunosuppressive therapy. Hormone therapy (e.g., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not
considered an excluded form of systemic treatment of an autoimmune disease.
10. Has a history of noninfectious pneumonitis that required steroids or a history of
interstitial lung disease.
11. Has a evidence of active, non-infectious pneumonitis.
12. Has a history of allogeneic tissue or solid organ transplant.
13. Has a active infection requiring systemic therapy.
14. Has a known history of HIV infection or any other relevant congenital or acquired
15. Has a known hepatitis B virus 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.