Clinical Trials Register

Summary
EudraCT Number:	2020-003947-27
Sponsor's Protocol Code Number:	TAK-981-1002
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-05-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Poland - Office for Medicinal Products

A.2

EudraCT number

2020-003947-27

A.3

Full title of the trial

An Open Label, Dose-Escalation, Phase 1/2 Study to Evaluate the Safety, Tolerability, Preliminary Efficacy, and Pharmacokinetics of TAK-981 in Adult Patients With Advanced or Metastatic Solid Tumors or Relapsed/Refractory Hematologic Malignancies

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Phase 1/2 Study to Evaluate the Safety, Tolerability, Preliminary Efficacy, and Pharmacokinetics of TAK-981 in Adult Patients With Solid Tumors or Hematologic Malignancies

A.4.1

Sponsor's protocol code number

TAK-981-1002

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Takeda Development Center Americas, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Takeda Development Center Americas, Inc. (TDC Americas)
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Takeda Pharmaceuticals International, Co
B.5.2	Functional name of contact point	Study Registration Center
B.5.3	Address:
B.5.3.1	Street Address	40 Landsowne Street
B.5.3.2	Town/ city	Cambridge, MA
B.5.3.3	Post code	02139
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 866 835 2233
B.5.6	E-mail	GlobalOncologyMedInfo@takeda.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TAK-981
D.3.2	Product code	TAK-981
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	1858276-04-6
D.3.9.2	Current sponsor code	TAK-981
D.3.9.4	EV Substance Code	SUB218403
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced or Metastatic Solid Tumors or Relapsed/Refractory Hematologic Malignancies

E.1.1.1

Medical condition in easily understood language

Solid Tumors or Hematologic Malignancies

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10066481
E.1.2	Term	Hematological malignancy
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase 1:To determine the safety and tolerability of TAK-981 as a single agent in patients with advanced or metastatic solid tumors and lymphomas. To establish the RP2D of TAK-981.
Phase 2:To evaluate preliminary efficacy of TAK-981 in patients with select solid tumors or relapsed/refractory CD20+ NHL indications

E.2.2

Secondary objectives of the trial

Phase 1:To assess the preliminary antitumor activity of TAK-981. To assess target engagement of TAK-981 (SUMO-TAK-981 adduct formation) and SUMOylation pathway inhibition in skin and peripheral blood cells. To characterize the PK profile of TAK-981.
Phase 2:To evaluate the efficacy of TAK-981 in select solid tumor and CD20+ NHL indications as measured by overall response rate (ORR), time to response (TTR),DOR, duration of the response (DOR), disease control rate (DCR), time to progression (TTP), and progression-free survival (PFS). To evaluate overall survival (OS). To evaluate the safety and tolerability of TAK-981.To collect plasma concentration-time data for TAK-981.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult male or female patients ≥18 years old.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Patient population for Phase 1 dose escalation:
a. Have a histologically or cytologically confirmed advanced or metastatic solid tumors who have no standard therapeutic option with a proven clinical benefit, are intolerant, or have refused them.
b. Have a relapsed/refractory lymphoma not amenable to therapies with proven clinical benefit or who are intolerant or who refuse them. Patients 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 patients 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, patients who need immediate therapy for tumor bulk are not eligible for this trial.
4. Patient population for Phase 2 dose expansion cohorts:
Have a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed below, which is incurable and for which prior standard first-line treatment has failed:
a.Nonsquamous NSCLC that has progressed to 1 prior systemic immune checkpoint inhibitor (CPI)/anti-PD-(1/L1)-containing therapy and no more than 2 lines of therapy. Patients 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).
b. CPI-naïve cervical cancer (squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix) patients who have received no more than 1 prior systemic line of therapy for recurrent or Stage IVB cervical cancer (cohort B).
c. CPI-naïve MSS-CRC patients who have progressed on no more than 3 chemotherapy regimens (cohort C).
d. Relapsed/refractory DLBCL progressed or relapsed after a prior CAR T-cell therapy that has received approval by a health authority for the treatment of DLBCL (Cohort D).
e. 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).
f. Relapsed/refractory FL that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic therapy. At least one 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 Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for patients 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.
6. In Phase 2 stage 1, willing to consent to mandatory pretreatment and on-treatment tumor biopsy.
7. Is willing to provide archival tumor tissue sample, if available.
8. Adequate bone marrow reserve and renal and hepatic function based on the following laboratory parameters:
a. Absolute neutrophil count (ANC) ≥1.0 × 109/L, hemoglobin ≥85 g/L (red blood cell transfusion allowed ≥14 days before assessment), and platelet count ≥75.0 × 109/L(platelet count ≥50.0 × 109/L is allowed for patients with lymphoma if it is clearly due to marrow involvement with no evidence of myelodysplastic syndrome or hypoplastic bone marrow, if found).
b. Total bilirubin ≤1.5 times the institutional upper limit of normal (ULN); or total bilirubin <3.0 times the ULN with direct bilirubin within normal range in patients with well documented Gilbert’s syndrome.
c. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 times the ULN (<5 times the ULN if liver enzyme elevations are due to liver metastases).
d. Estimated creatinine clearance using the Cockcroft-Gault formula ≥45 mL/min.
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, or bone marrow parameters [any of Grade 1/2 permitted if directly related to bone marrow involvement]).
10. Consented to undergo serial skin punch biopsies .
11. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
12. Suitable venous access for safe drug administration and the study-required PK and pharmacodynamic sampling.
13. Women of childbearing potential participating in this study should avoid becoming pregnant
See 14. Male patients contraception more details set out in protocol

E.4

Principal exclusion criteria

1. Phase 1 dose escalation and Phase 2 cancer treatment expansion cohorts:
a. Have 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.
b. Have received extended field radiotherapy ≤4 weeks before the start of treatment (≤2 weeks for limited field radiation for palliation) and have not recovered to Grade 1 or baseline from related side effects of such therapy (except for alopecia).
2. Have a history of uncontrolled brain metastasis. Patients with brain metastases are allowed if they are previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery and the patients are receiving a corticosteroid dose ≤10 mg/day of prednisone equivalent at the time of receiving the first dose of TAK-981. For asymptomatic patients, screening brain imaging is not required.
3. Patient is receiving any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation of study treatment.
4. 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 (eg, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.
5. Baseline prolongation of the QT interval with Fridericia correction method (QTcF) (eg, repeated demonstration of QTcF interval >480 ms, history of congenital long QT syndrome, or torsades de pointes).
6. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.
7. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
8. 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 (eg, 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
9. History of immune-related AEs related to treatment with immune checkpoint inhibitors that required treatment discontinuation.
10. History of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
11. Has evidence of active, noninfectious pneumonitis.
12. Have a significant active infection.
13. Known history of human immunodeficiency virus infection or any other relevant congenital or acquired immunodeficiency.
14. Known hepatitis B virus (HBV) surface antigen seropositive or detectable hepatitis C infection viral load.
15. Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and inducers of CYP3A4/5 or are strong P-gp inhibitors at screening. To participate in this study, such patients should discontinue use of such agents for at least 2 weeks (1 week for CUP3A4/5 and P-gp inhibitors) or 5 times the half-life
(whichever is shorter) before receiving a dose of TAK-981.
16. Patient requires the use of drugs known to prolong QTc interval (during Phase 1 only) (Appendix H).
17. History of allogeneic tissue or solid organ transplant.
18. 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 patient is not on active anticancer therapy.
19. Female patients 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.

E.5 End points

E.5.1

Primary end point(s)

Phase 1:
Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 except CRS, which will be graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS.
DLTs within the first 21 days of treatment in Cycle 1.
Phase 2:
ORR (complete response [CR] + partial response [PR]) as defined by the investigator according to RECIST v1.1 criteria for solid tumors or Lugano classification for lymphomas.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase 1 and 2

E.5.2

Secondary end point(s)

PK parameters after the first dose of TAK-981 on C1D1 and C1D8 (data permitting):
– Maximum observed plasma concentration (Cmax).
– Time of first occurrence of maximum observed plasma concentration (tmax).
– Area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUClast).
– Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).
– Terminal disposition phase half-life (t1/2z).
– Total clearance (CL) after IV administration.
– Vss.
Phase 1:
ORR, DCR, DOR, TTP, and PFS as assessed by the investigator according to RECIST v1.1 criteria for solid tumors or Lugano classification for lymphomas.
TAK-981-SUMO adduct formation and SUMO pathway inhibition in skin/blood.
Phase 2:
Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups according to the NCI CTCAE version 5.0; except CRS which will be graded according to ASTCT Consensus Grading for CRS.
DCR, DOR, TTR, TTP and PFS, and OS as assessed by the investigator according to RECIST v1.1 criteria for solid tumors or Lugano classification for lymphomas and OS.

E.5.2.1

Timepoint(s) of evaluation of this end point

After the first dose of TAK-981, phase 1 and 2

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase 1 occurs only in USA

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Ph1: cohort-based dose escalation with an adaptive design. Phase 2: 6 treatment cohorts of patients

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Phase 1 (dose escalation), Phase 2 is a cancer treatment dose expansion with 6 treatment arms

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Information not present in EudraCT

E.8.4

The trial involves multiple sites in the Member State concerned

Information not present in EudraCT

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

China

United States

Poland

Romania

Spain

Belgium

Ukraine

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The primary analyses for the primary endpoint will be conducted after all patients enrolled in the study have had the opportunity to complete 9 cycles of treatment with TAK-981. The final data cutoff for the clinical study report will be conducted after all patients have been discontinued from
treatment or transferred to a long-term safety study, a single-patient investigational new drug application, or a similar program.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

132

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Participants may continue to receive TAK-981 in an extension phase of this study or will be given the opportunity to enroll in a separate open-label rollover study or have the possibility of using an individual patient investigational new drug to continue receiving TAK-981. Additionally, these patients should have no alternative therapeutic option, and would be harmed without continued access.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-07-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-12-14

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