Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Breast Neoplasms

Pancreatic Neoplasms

Prostatic Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urogenital Neoplasms

Genital Diseases

Urogenital Diseases

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Endocrine System Diseases

Gonadal Disorders

Breast Diseases

Skin Diseases

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Pancreatic Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Antineoplastic Agents

All Drugs and Chemicals

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Participants with BRCA 1/2 mutant or HRD+ solid tumors will receive escalating doses of TNG348 to estimate the MTD

Participants with BRCA 1/2 mutant or HRD+ solid tumors will receive escalating doses of TNG348 in combination with olaparib to estimate the MTD

Participants with BRCA 1/2 mutant breast cancer will receive TNG348 at the identified RP2D

Participants with BRCA 1/2 mutant ovarian cancer will receive TNG348 at the identified RP2D

Participants with BRCA 1/2 mutant breast cancer will receive TNG348 in combination with olaparib at the identified RP2D

Participants with BRCA 1/2 mutant ovarian cancer will receive TNG348 in combination with olaparib at the identified RP2D

Participants with BRCA 1/2 mutant pancreatic or prostate cancer will receive TNG348 in combination with olaparib at the identified RP2D

Participants with HRD+ advanced or metastatic solid tumors will receive TNG348 in combination with olaparib at the identified RP2D

Ubiquitin Specific Peptidase 1 (USP1) inhibitor

TNG348

Tiffany Wang, MD

The goal of this interventional clinical trial is to learn about TNG348, a ubiquitin specific peptidase 1 (USP1) inhibitor, alone and in combination with olaparib in patients with BRCA 1/2 mutant or HRD+ solid tumors.

The main question\[s\] it aims to answer are:

* to evaluate the safety and tolerability of single agent and combination therapy
* to determine the recommended dose for Phase 2 of single agent and combination therapy
* to determine the pharmacokinetics of TNG348 as a single agent and in combination therapy
* to evaluate the initial antineoplastic activity as a single agent and in combination therapy

Participants will receive study treatment until they experience an undesirable side effect, their disease progresses or until they withdraw consent.

This is a first-in-human Phase 1/2, open-label, multi-center, dose-escalation and expansion study designed to determine the maximum-tolerated dose (MTD) and recommended Phase 2 dose(s) (RP2D) and evaluate the safety, tolerability, and preliminary antitumor activity of TNG348 single agent and in combination with olaparib in participants with BRCA1/2 mutant or other HRD+ advanced or metastatic solid tumors.

In Phase 1 (dose escalation), the single agent component will explore escalating oral doses of TNG348 administered alone and in combination with olaparib.

Participants in Phase 2 (dose expansion) will be dosed at the RP2D(s) determined from Phase 1 based on safety and tolerability demonstrated, along with the available PK data and studied during Phase 1, as applicable.

In the Phase 2 portion of the study, both single agent and combination therapy may be evaluated to assess an early signal of clinical benefit, as well as for confirmation of safety and tolerability.

Phase 1 Dose Escalation and Phase 2 Dose Expansion

Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors

Phase 1/2, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Antitumor Activity of TNG348 Single Agent and in Combination With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or Other HRD+ Solid Tumors

• To determine the MTD, RP2D(s), and dosing schedule of TNG348 single agent and in combination with olaparib

To assess the antitumor activity of TNG348 single agent and in combination using RECIST 1.1 per investigator assessment

Measure frequency, severity, timing, and relationship to study treatment of any AEs, SAEs, and changes in safety laboratory tests

To determine the AUC0-t and AUC0-∞ of TNG348

To characterize the pre treatment and trough concentration levels of olaparib when administered in combination with TNG348

Measure ubPCNA in tumor tissue and blood, on study treatment relative to pre-treatment

Tango Therapeutics, Inc.

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Niraparib

Adenosine

Placebo

GSK Clinical Trials

This study aims to assess efficacy of Niraparib (GSK3985771) as maintenance treatment in participants with Stage III or IV ovarian cancer. Participants must have completed front-line platinum based regimen with complete response (CR) or partial response (PR). Data collection for Secondary Outcome measures is ongoing and the approximate duration of the study will be 7 years.

A Study of Niraparib (GSK3985771) Maintenance Treatment in Participants With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy

An adverse event is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly or birth defect or any other situation according to medical or scientific judgment was categorized as SAE.

Blood samples were planned to be collected for assessment of AUC(0-last).

Blood samples were planned to be collected for assessment of Cmax.

Number of participants with positive HRD test was planned to be assessed.

Progression free survival was defined as the time from the date of treatment randomization to the date of first documentation of disease progression or death due to any cause in the absence of documented progression, whichever occurs first. It was assessed by the blinded independent central review (BICR). Median and 95% confidence interval (CI) are presented.

Overall survival was defined as the time from the date of randomization to the date of death by any cause. Median and 95% CI are presented for overall survival interim analysis.

Time to first subsequent therapy was defined as the time from the date of randomization to the date of the first subsequent anti-cancer therapy or death, whichever occurs first. Median and 95% CI are presented.

PFS2 was defined as the time from the date of randomization to the date of progression on the next anti-cancer therapy following study treatment or death by any cause, whichever occurs first. Median and 95% CI are presented.

FOSI is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants responded to their symptom experience over the past 7 days using a 5-point Likert scale scored from "not at all" (0) to "very much" (4). FOSI score was calculated as (sum of item scores)\*8 divided by (number of items answered). The FOSI score ranged from 0 (severely symptomatic) to 32 (asymptomatic). A higher score indicated a better quality of life (QoL). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-dose assessment (Day 1 pre-dose).

The EQ-5D-5L is a well-validated general preference-based, health-related QoL instrument. The five-item measure has 1 question assessing each of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and 5 levels for each dimension including 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. The health state is defined by combining the levels of answers from each of the 5 questions. Each health state is referred to in terms of a 5 digit code. Health state 5 digit code is translated into utility score, which is valued up to 1 (perfect health) with lower values meaning worse state. EQ-5D-5L utility score ranges from -0.281 to 1. Higher scores indicate better health. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-dose assessment (Day 1 pre-dose).

EORTC-QLQ-C30 incorporates 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), a global health status/QoL scale (global health status, QoL), and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulty) assessing additional symptoms commonly reported by participants with cancer. Five functional scales had total 15 items (physical-5, role-2, cognitive-4, emotional-2, and social-2). Each functional scales score was calculated by averaging scores of all scale items and transforming average scores linearly (1 minus \[average score minus 1\] divided by 3\*100). All of the functional scales range in score from 0 to 100. Higher score represents a higher ("better") level of functioning. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-dose assessment (Day 1 pre-dose).

EORTC-QLQ-C30 incorporates 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), a global health status/QoL scale (global health status, QoL), and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulty) assessing additional symptoms commonly reported by participants with cancer. A global health status/QoL scale had total 2 items. Each global health status/QoL scales score was calculated by averaging scores of all scale items and transforming average scores linearly (\[average score minus 1\] divided by 6\*100). The global health status/QoL scales range in score from 0 to 100. Higher score represents a higher ("better") level of health status/QoL. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-dose assessment (Day 1 pre-dose).

EORTC-QLQ-C30 incorporates 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), a global health status/QoL scale, and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulty) assessing additional symptoms commonly reported by participants with cancer. Symptom scale had total 7 items (fatigue-3, pain-2, nausea/vomiting-2). Each symptoms scales and 6 single additional symptoms items score was calculated by averaging scores of all scale items and transforming average scores linearly (\[average score minus 1\] divided by 3\*100). All of the symptoms scales and 6 single additional symptoms scales range in score from 0 to 100. Higher score represents a higher ("worse") level of symptoms. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-dose assessment (Day 1 pre-dose).

EORTC-QLQ-OV28 is supplement to EORTC-QLQ-C30. It includes 3 functional scales (body image, sexuality, attitude to disease/treatment) and 5 symptom scales/items (abdominal/gastrointestinal \[GI\] symptoms, peripheral neuropathy, hormonal/menopausal symptoms, other chemotherapy side-effects, and hair loss). Functional scales score (body Image and attitude to disease/treatment) was calculated by averaging scores of all scale items and transforming average scores linearly (1 minus \[average score minus 1\] divided by 3\*100). Functional scales score (sexuality) was calculated by averaging scores of all scale items and transforming average scores linearly (\[average score minus 1\] divided by 3\*100). All of the functional scales range in score from 0 to 100. Higher score represents a higher ("better") level of functioning. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-dose assessment (Day 1 pre-dose).

EORTC-QLQ-OV28 is supplement to EORTC-QLQ-C30. It includes 3 functional scales (body image, sexuality, attitude to disease/treatment) and 5 symptom scales/items (abdominal/GI symptoms, peripheral neuropathy, hormonal/menopausal symptoms, other chemotherapy side-effects, and hair loss). Symptoms scales score was calculated by averaging scores of all scale items and transforming average scores linearly (\[average score minus 1\] divided by 3\*100). All of the symptoms scales range in score from 0 to 100. Higher score represents a higher ("worse") level of symptoms. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Baseline was defined as the latest pre-dose assessment (Day 1 pre-dose).

Gynecologic Oncology Group

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Myriad Genetics, Inc.

Tesaro, Inc.

Non-SAEs and SAEs were presented for Safety Population. 5 participants out of 733 participants did not receive any study treatment and were excluded from the Safety Population. The results presented are based on the primary analysis up to month 34. Data collection is still on-going and additional results will be provided after study completion (7 years).

Participants received placebo matching niraparib 300 milligram (mg) (3×100 mg capsules) (fixed dose) once daily (QD) orally beginning on Day 1 of every cycle (each cycle of 28-days) in a double-blind fashion until a modified starting dose regimen was implemented in protocol amendment. After the protocol amendment, participants received placebo based upon the participant's Baseline body weight or Baseline platelet count (individualized dose): 300 mg (3×100 mg capsules for participants with a Baseline body weight \>=77 kilogram \[kg\] and Baseline platelet count \>=150,000 per microliter \[μL\]) or 200 mg (2×100 mg capsules for participants with a Baseline body weight \<77 kg or Baseline platelet count \<150,000 per μL).

Participants received niraparib 300 mg (3×100 mg capsules) (fixed dose) QD orally beginning on Day 1 of every cycle (each cycle of 28-days) in a double-blind fashion until a modified starting dose regimen was implemented in protocol amendment. After the protocol amendment, participants received niraparib based upon the participant's Baseline body weight or Baseline platelet count (individualized dose): 300 mg (3×100 mg capsules for participants with a Baseline body weight \>=77 kg and Baseline platelet count \>=150,000 per μL) or 200 mg (2×100 mg capsules for participants with a Baseline body weight \<77 kg or Baseline platelet count \<150,000 per μL).

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Baseline characteristics were presented for all randomized participants including 5 randomized participants who never received treatment (4-Screen failure and 1-Withdrew consent).

GSK Response Center

Intent-to-Treat (ITT) population comprised of all participants who were randomized into the study.

Progression Free Survival

Overall Survival

Time to First Subsequent Therapy (TFST)

Progression-Free Survival-2 (PFS2)

ITT Population. Only those participants with data available at the specified time points were analyzed.

Change From Baseline in Participant Reported Outcome (PRO): Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI)

Change From Baseline in PRO: European Quality of Life Scale, 5-dimensions, 5-levels of Severity (EQ-5D-5L) Utility Score

Physical Functioning, n=244,479

Role Functioning, n=244,479

Emotional Functioning, n=243,478

Cognitive Functioning, n=243,478

Social Functioning, n=243,478

ITT Population. Only those participants with data available at the specified time points were analyzed (represented by n= X in the category titles).

Change From Baseline in Functional Scales of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC-QLQ-C30)

Change From Baseline in Global Health Status/QoL of EORTC-QLQ-C30

Fatigue, n=243,479

Nausea/Vomiting, n=244,479

Pain, n=244,480

Dyspnea, n=244,479

Insomnia, n=244,479

Appetite Loss, n=8,30

Constipation, n=244,478

Diarrhea, n=8,30

Financial Difficulties, n=243,475

Change From Baseline in Symptoms Scales and Symptoms Items (Dyspnea, Appetite Loss, Insomnia, Constipation, Diarrhea and Financial Difficulty) of EORTC-QLQ-C30

Body Image, n=244,475

Sexuality, n=240,471

Attitude to disease/Treatment, n=244,475

Change From Baseline in Functional Scales of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Ovarian Cancer Module (EORTC-QLQ-OV28)

Abdominal/GI, n=244,481

Peripheral Neuropathy, n=244,480

Hormonal/Menopausal Symptoms, n=244,480

Other Chemotherapy Side Effects, n=244,480

Hair Loss, n=242,477

Change From Baseline in Symptoms Scale of EORTC-QLQ-OV28

Any non-SAE

Any SAE

Safety Population comprised of all participants who received at least 1 dose of study drug. 5 participants (2 participants from Placebo group and 3 participants from Niraparib group) out of 733 participants did not receive any study treatment and thus, were excluded from the Safety Population.

Number of Participants With Any Non-serious Adverse Event (Non-SAE) or Any SAE

ITT Population. This was an other pre-specified outcome measure. Data will not be analyzed and reported.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors	NCT06065059	Breast Cancer Ovarian Cancer Pancreas Cancer Prostate Cancer BRCA1 Mutation BRCA-Mutated Ov... BRCA-Associated... HRD Positive Ad...	TNG348 Olaparib	18 Years -	Tango Therapeutics, Inc.
Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors	NCT06065059	Breast Cancer Ovarian Cancer Pancreas Cancer Prostate Cancer BRCA1 Mutation BRCA-Mutated Ov... BRCA-Associated... HRD Positive Ad...	TNG348 Olaparib	18 Years -	Tango Therapeutics, Inc.
A Study of Niraparib (GSK3985771) Maintenance Treatment in Participants With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy	NCT02655016	Ovarian Neoplas...	Niraparib Placebo	18 Years -	Tesaro, Inc.

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