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Antineoplastic Agents, Immunological

Patients were treated with MIW815 (ADU-S100) via intratumoral injection for 3 weeks followed by one week off in combination with a fixed intravenous dose of PDR001 given once per month

Patients were treated with MIW815 (ADU-S100) via intratumoral injection given once a month in combination with a fixed intravenous dose of PDR001 given once per month

MIW815

PDR001

Nancy Lewis, MD

The purpose of this study was to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of MIW815 (ADU-S100) in combination with PDR001.

This was a Phase Ib, multi-center, open-label study to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of MIW815(ADU-S100) in combination with the PD-1 checkpoint inhibitor PDR001. Two different schedules were explored in two dose escalation groups in accessible cutaneous or subcutaneous lesions. The optional dose confirmation group exploring intratumoral injection of viscerally located lesions was not opened due to the program's early termination.

Group A included patients with accessible solid tumors and lymphomas. This group received a fixed dose of PDR001 i.v. on day 1 of every 28 day cycle and intratumoral injections of MIW815 (ADU-S100) on days 1, 8 and 15 of every 28 day cycle. Group B included patients with accessible solid tumors and lymphomas. This group received a fixed dose of PDR001 i.v. on day 1 of every 28 day cycle and an intratumoral injection of MIW815 (ADU-S100) on day 1 of every 28 day cycle.

Once the dose and dose schedule had been confirmed, the plan was to open the dose expansion part of the study. However, the expansion phase of the study was not opened to enrollment due to the program's early termination.

The study was comprised of two treatment arms.

Group A included patients with accessible solid tumors and lymphomas. This group received a fixed dose of PDR001 intravenous on day 1 of every 28 day cycle and intratumoral injections of MIW815 (ADU-S100) on days 1, 8 and 15 of every 28 day cycle.

Group B included patients with accessible solid tumors and lymphomas. This group received a fixed dose of PDR001 intravenous on day 1 of every 28 day cycle and an intratumoral injection of MIW815 (ADU-S100) on day 1 of every 28 day cycle.

Once the maximum tolerated dose and/or recommended dose for expansion had been determined, the plan was to open the expansion part of the study. However, the dose expansion phase of the study was not opened to enrollment due to the program's early termination.

Study of the Safety and Efficacy of MIW815 With PDR001 in Patients With Advanced/Metastatic Solid Tumors or Lymphomas

A Phase Ib, Open Label, Multicenter Study of the Safety and Efficacy of MIW815 (ADU-S100) Administered by Intratumoral Injection With PDR001 to Patients With Advanced/Metastatic Solid Tumors or Lymphomas

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment with the combination of MIW815 (ADU-S100) and PDR001

The area under the concentration-time curve extrapolated to infinity (mass\*time/volume)

The area under the concentration (AUC) -time curve calculated to the last quantifiable concentration point (mass\* time/volume)

Area under the concentration-time curve calculated to the end of the dosing interval (tau) (mass\* time/volume)

The time to reach the maximum observed concentration (time)

The maximum observed concentration (Cmax) following dose administration (mass/volume)

Terminal elimination rate constant (1/time)

Apparent systemic clearance of drug from the plasma (volume x time -1)

Elimination half-life, determined as 0.693/Lambda_z (time)

Apparent volume of distribution during the terminal elimination phase (volume)

Overall response rate will be summarized with accompanying 90% exact binomial confidence interval (CI).

The survival function will be estimated using the Kaplan-Meier product limit method. Median duration, with a two-sided Brookmeyer-Crowley 90% confidence interval and Kaplan-Meier estimates of survival proportions will be provided at specified time points.

The disease control rate is calculated as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease

Time To Response is the time from first dose to first documented response (CR or PR). TTR will be summarized

Duration of response is defined as the time from the date of the first documented response (CR or PR), to the date of first documented progression, or death due to study indication. Estimates will use Kaplan-Meier method

Induction of TILs in the injected lesion (local PD effect) and in a non-injected lesion (distal PD effect) will be assessed using paired tumor samples at screening and on-treatment.

Novartis Pharmaceuticals

Skin and Connective Tissue Diseases

Breast Neoplasms

Fulvestrant

Exemestane

Estrogens

Antineoplastic Agents, Hormonal

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Aromatase Inhibitors

Enzyme Inhibitors

Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 0.6 mg to determine the MTD.

Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 1.4 mg to determine the MTD.

Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 2 mg to determine the MTD.

Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 3 mg to determine the MTD.

Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 4 mg to determine the MTD.

Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 6 mg to determine the MTD.

Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with exemestane 25 mg.

Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with fulvestrant 500 mg.

Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 3 mg in combination with fulvestrant 500 mg.

Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle

Alobresib

Tablets administered orally once daily on Cycle 1 Day 1 of 28 days cycle

Administered intramuscularly on Cycle 1 Day 1 of 28 days cycle and every 28 days

Gilead Study Director

The primary objectives of this study are to characterize the safety and tolerability and determine the maximum tolerated dose (MTD) or recommended dose for phase 2 study (RDP2) of alobresib as a monotherapy in participants with advanced solid tumors and lymphomas, and in combination with exemestane or fulvestrant in participants with advanced estrogen receptor positive breast cancer.

Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alobresib (Formerly GS-5829) in Adults With Advanced Solid Tumors and Lymphomas and in Combination With Exemestane or Fulvestrant in Adults With Estrogen Receptor Positive Breast Cancer

A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alobresib (Formerly GS-5829) as a Monotherapy in Subjects With Advanced Solid Tumors and Lymphomas and in Combination With Exemestane or Fulvestrant in Subjects With Estrogen Receptor Positive Breast Cancer

A DLT was a toxicity, considered possibly related to alobresib, and which occurred during DLT assessment window (Day 1 through Cycle 1 Day 28) in each cohort: Grade ≥ 4 neutropenia (absolute neutrophil count \[ANC\] \< 500/mm\^3); Grade ≥3 neutropenia (ANC\< 1000/mm\^3) with fever (a single temperature of \> 38.3°C or a sustained temperature of ≥ 38°C for more than 1 hour \[hr\]); Grade ≥ 3 thrombocytopenia; Grade ≥ 2 bleeding; Grade ≥ 3 non hematologic toxicity, except Grade 3 nausea or emesis with maximum duration of 48 hrs on adequate medical therapy and Grade 3 diarrhea which persists for \< 72 hrs in absence of maximal medical therapy; Grade ≥ 2 non hematologic treatment-emergent adverse event (TEAE) of potential clinical significance; treatment interruption ≥ 7 days due to unresolved toxicity; and any Grade 3 or 4 elevation in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) associated with a Grade 2 elevation in bilirubin that is at least possibly related to alobresib.

Cmax is defined as the maximum concentration of the drug.

Ctau is defined as the observed drug concentration at the end of the dosing interval.

AUC0-24 is defined as the concentration of drug over time from time zero to time 24 hrs.

AUCtau is defined as the concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Tmax is defined as the time (observed time point) of Cmax.

t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Due to short sampling period of the terminal elimination phase in these cohorts t1/2 values should be interpreted with caution.

Gilead Sciences

The Full Analysis Set included all participants who received at least 1 dose of study drug.

Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 0.6 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD.

Monotherapy: Alobresib 0.6 mg

Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 1.4 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD.

Monotherapy: Alobresib 1.4 mg

Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 2 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD.

Monotherapy: Alobresib 2 mg

Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 3 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD.

Monotherapy: Alobresib 3 mg

Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 4 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD.

Monotherapy: Alobresib 4 mg

Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 6 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD.

Monotherapy: Alobresib 6 mg

Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy existed, received alobresib tablets at a dose of 2 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle in combination with exemestane 25 mg tablets administered orally once daily on C1D1 of 28 days cycle.

Combination Therapy: Alobresib 2 mg + Exemestane

Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy existed, received alobresib tablets at a dose of 2 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle in combination with fulvestrant 500 mg administered intramuscularly on C1D1 of 28 days cycle and every 28 days (± 3 days).

Combination Therapy: Alobresib 2 mg + Fulvestrant

Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy existed, received alobresib tablets at a dose of 3 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle in combination with fulvestrant 500 mg administered intramuscularly on C1D1 of 28 days cycle and every 28 days (± 3 days).

Combination Therapy: Alobresib 3 mg + Fulvestrant

Total

Age, Categorical

Sex: Female, Male

Ethnicity

Race/Ethnicity, Customized

Race

Gilead Clinical Study Information Center

Number of Participants Experiencing Dose Limiting Toxicities (DLTs)

Cycle 1 Day 1

Cycle 1 Day 8

Participants in the PK Analysis Set (included all enrolled participants who took at least 1 dose of study drug and had at least 1 nonmissing postdose value reported by the PK laboratory) with available data were analyzed.

Pharmacokinetic (PK) Parameter: Cmax of Alobresib

Participants in the PK Analysis Set with available data were analyzed.

PK Parameter: Ctau of Alobresib

PK Parameter: AUC0-24 of Alobresib

PK Parameter: AUCtau of Alobresib

PK Parameter: Tmax of Alobresib

PK Parameter: t1/2 of Alobresib

Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 0.6 mg orally once daily on Study Day 1 through Cycle 1 Day 28 (C1D28) of 28 days cycle to determine the maximum tolerated dose (MTD).

Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy existed, received alobresib tablets at a dose of 2 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle in combination with exemestane 25 mg tablets administered orally once daily on Cycle 1 Day 1 (C1D1) of 28 days cycle.

Overall Study

GMX1777

Mark Berger, MD

GMX1777 is a water-soluble, intravenously-administered prodrug of GMX1778. GMX1777 is rapidly converted to GMX1778 in vivo. GMX1778 has potent anti-tumor activity against a variety of cell lines and models from different tumor origins.

This is a single-center, open-label, Phase I study of single-agent GMX1777 administered every 3 weeks to patients with CLL, MM, refractory solid tumors or lymphomas. No investigational or commercial agents or therapies other than those described may be administered with the intent to treat the patient's malignancy.

Safety and Efficacy of GMX1777 in the Treatment of Refractory Solid Tumors or Lymphomas

A Single-Center, Open-Label, Phase I Study of Single-Agent GMX1777 Administered as a 24-Hour Infusion Every 3 Weeks to Patients With Refractory Solid Tumors or Lymphomas

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of the Safety and Efficacy of MIW815 With PDR001 in Patients With Advanced/Metastatic Solid Tumors or Lymphomas	NCT03172936	Solid Tumors an...	MIW815 PDR001	18 Years -	Novartis
Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alobresib (Formerly GS-5829) in Adults With Advanced Solid Tumors and Lymphomas and in Combination With Exemestane or Fulvestrant in Adults With Estrogen Receptor Positive Breast Cancer	NCT02392611	Solid Tumors an...	Alobresib Exemestane Fulvestrant	18 Years -	Gilead Sciences
Safety and Efficacy of GMX1777 in the Treatment of Refractory Solid Tumors or Lymphomas	NCT00457574	Solid Tumors an...	GMX1777	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.
Study of the Safety and Efficacy of MIW815 With PDR001 in Patients With Advanced/Metastatic Solid Tumors or Lymphomas	NCT03172936	Solid Tumors an...	MIW815 PDR001	18 Years -	Novartis
Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alobresib (Formerly GS-5829) in Adults With Advanced Solid Tumors and Lymphomas and in Combination With Exemestane or Fulvestrant in Adults With Estrogen Receptor Positive Breast Cancer	NCT02392611	Solid Tumors an...	Alobresib Exemestane Fulvestrant	18 Years -	Gilead Sciences

Spots Global Cancer Trial Database for solid tumors and lymphomas