Antineoplastic Agents

All Drugs and Chemicals

Cisplatin

Alpelisib: 200 mg/day, orally, days 1-21 Cisplatin: 30 mg/m\^2, intravenously, days 1, 8, 15

Alpelisib: 250 mg/day, orally, days 1-21 Cisplatin: 30 mg/m\^2, intravenously, days 1, 8, 15

Alpelisib: 250 mg/day, orally, days 1-21 Cisplatin: 35 mg/m\^2, intravenously, days 1, 8, 15

Alpelisib: 300 mg/day, orally, days 1-21 Cisplatin: 30 mg/m\^2, intravenously, days 1, 8, 15

Alpelisib: 300 mg/day, orally, days 1-21 Cisplatin: 35 mg/m\^2, intravenously, days 1, 8, 15

Alpelisib: 350 mg/day, orally, days 1-21 Cisplatin: 30 mg/m\^2, intravenously, days 1, 8, 15

Alpelisib: 350 mg/day, orally, days 1-21 Cisplatin: 35 mg/m\^2, intravenously, days 1, 8, 15

Alpelisib

Pamela Munster, MD

This phase Ib trial studies the best dose and side effects of alpelisib and cisplatin in treating patients with human papillomavirus (HPV) positive solid tumor malignancies. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving alpelisib and cisplatin may work better in treating patients with solid tumor malignancies.

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose and recommended phase 2 dose of alpelisib in combination with weekly cisplatin.

SECONDARY OBJECTIVES:

I. To determine the objective response rate and median progression-free survival with the treatment combination in HPV positive (+) solid tumor malignancies.

II. To characterize the safety profile of the combination.

OUTLINE: This is a dose escalation study.

Patients receive alpelisib orally (PO) once daily (QD) on days 1-14 or 1-21, and cisplatin intravenously (IV) over 1-2 hours on days 1 and 8, or days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Phase Ib Study of Alpelisib With Cisplatin in Patients With HPV+ Solid Tumor Malignancies

A Phase Ib, Open-label Study of Alpelisib (BYL719) in Combination With Cisplatin in Patients With HPV+ Solid Tumor Malignancies

Pamela Munster

Professor

Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Melanoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Transitional Cell

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Lung Neoplasms

Melanoma, Cutaneous Malignant

Skin Neoplasms

Ureteral Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Carcinoma, Bronchogenic

Bronchial Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Ureteral Diseases

Urologic Diseases

Male Urogenital Diseases

Transitional Cell Carcinoma

Neuroendocrine Tumor

Neuroepithelioma

Pembrolizumab

Abexinostat

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Histone Deacetylase Inhibitors

Enzyme Inhibitors

Participants receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Participants with primary resistance to prior anti-PD-1/PD-L1 will receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Participants with acquired resistance, defined as treatment duration on prior CPI for greater than 6 months with evidence of clinical benefit (tumor regression or disease stabilization) with subsequent disease progression will receive abexinostat PO BID on days -7 to -4 of the lead-in period, and days 1-4, 8-11 of each treatment cycle and pembrolizumab over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Given orally (PO) twice a day (BID) days 1-4, 8-11 of every 21 day cycle

Rahul Aggarwal, MD

This phase I trial studies the best dose and side effects of abexinostat and how well it works with given together with pembrolizumab in treating participants with microsatellite instability (MSI) solid tumors that have spread to other places in the body. Abexinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving abexinostat and pembrolizumab may work better in treating participants with solid tumors.

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated and recommended phase 2 dose of abexinostat in combination with anti-PD-1/PD-L1 checkpoint inhibitor (CPI). (Dose escalation)

II. To determine the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients treated with abexinostat in combination with CPI in patients with prior primary (cohort A) or acquired (cohort B) resistance to prior CPI treatment. (Dose expansion)

SECONDARY OBJECTIVES:

I. To determine the objective response rate and median duration of response (DoR) by immune modified (i)RECIST criteria.

II. To determine the median progression-free survival (PFS).

III. To further characterize the safety profile of the treatment combination.

OUTLINE: This is a dose-escalation study of abexinostat.

Participants receive abexinostat orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) on over 30 minutes day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 90 days.

Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies

A Phase 1b Dose Escalation/Expansion Study of Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies

Starting at dose level 1, if 2/3 patients have a dose-limiting toxicity (DLT), the dose will be de-escalated to dose -1. If 0/3 patients experience a DLT, 3 patients will be treated at the next dose level. If DLT attributable to the treatment is experienced in 1/3 patients, three more patients (for a total of six patients) will be treated at that dose level. If no additional DLTs are observed at the expanded dose level (i.e. 1/6 with DLT), the dose will be escalated. Escalation will terminate as soon as two or more patients experience any DLT attributable to study drugs, at a given dose level. If de-escalation is necessary, 3 patients will be enrolled on the next lower dose cohort. If 1 or less DLTs is observed in this cohort, this will be the MTD.

Objective response rate (ORR) by RECIST 1.1 criteria in patients treated with abexinostat in combination with (CPI) immune checkpoint inhibition in patients with prior primary or acquired resistance to prior CPI treatment.

Objective response rate (ORR) by iRECIST. The criteria are identical to those of RECIST 1.1 but have been adapted to account for instances where an increase in tumor burden, or the appearance of new lesions, does not reflect true tumor progression. Immuno response evaluation criteria in solid tumours (iRECIST) ORR requires the confirmation of progression and uses the terms unconfirmed progression (iUPD) and confirmed progression (iCPD).

The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR), whichever is first recorded, until the first date that recurrent or progressive disease is objectively documented.

The duration of overall response is measured from the time measurement criteria are met for CR (complete response) or PR (partial response), whichever is first recorded, until the first date that recurrent or progressive disease is objectively documented. The criteria are identical to those of RECIST 1.1 but have been adapted to account for instances where an increase in tumor burden, or the appearance of new lesions, does not reflect true tumor progression. iRECIST requires the confirmation of progression and uses the terms iUPD (unconfirmed progression) and iCPD (confirmed progression).

PFS is defined as the time from the date of initiation of study treatment to the date measurement criteria are first met for radiographic progressive disease (PD) or death from any cause, whichever occurs first.

Percentages of participants experiencing adverse events by preferred term will be summarized by NCI-CTCAE version 5

Xynomic Pharmaceuticals, Inc.

Rahul Aggarwal

Assistant Professor of Hematology/Oncology

Symptoms and General Pathology

Gland and Hormone Related Diseases

Breast Neoplasms

Recurrence

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Genomic Instability

Breast Diseases

Disease Attributes

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Genital Neoplasms, Female

Endocrine System Diseases

Gonadal Disorders

Ovarian Cancer

Ovarian Epithelial Cancer

Participants receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants with disease progression may continue pembrolizumab for up to 1 year.

Laboratory Biomarker Analysis

Eugenia Girda, MD

Eugenia M. Girda, MD

Janice Mehnert, MD

This phase II trial studies how well pembrolizumab works in treating participants with cancer that has spread to other places in the body, has come back or has spread to nearby tissues or lymph nodes. Monoclonal antibodies such as, pembrolizumab, may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVES:

I. To evaluate the response rate of pembrolizumab in participants with evidence of genomic instability who have solid tumors with POLE and POLD1 mutations.

II. To evaluate the response rate of pembrolizumab in participants with evidence of genomic instability who have solid tumors with BRCA1/2 mutations.

SECONDARY OBJECTIVES:

I. To compare the complete and partial response rate, and response durability (immune related progression free survival), to historical cohort information of unselected patients treated with pembrolizumab.

TERTIARY OBJECTIVES:

I. To evaluate the CD4+ and CD8+ T cell response in the tumor microenvironment and peripheral blood of patients treated on this study as well as the frequencies, activation/differentiation, functionality, and co-inhibitory molecule expression of immune cell populations in peripheral blood and tumor, before and after treatment with systemic pembrolizumab.

II. To measure PD-L1 expression in pretreatment tumor biopsies and in post treatment tumor tissue, as well as on biopsies taken at progression, to capture data on the relationship between PD-L1 expression and patient outcome.

III. To perform deep sequencing for detection of PD-1 and PD-L1 polymorphisms that may correlate with clinical outcomes as well as identification of mutations in immunoregulatory genes that are potential predictors of response to these therapies.

IV. To perform exome sequencing of pre-treatment tumor specimens to determine if the presence of immunogenic neoantigens is associated with response.

V. To perform ribonucleic acid (RNA) sequencing to determine if expression of checkpoint genes, immune-regulatory modules, or non-coding RNAs including repetitive RNAs and retroelements are associated with response.

OUTLINE:

Participants receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants with disease progression may continue pembrolizumab for up to 1 year.

After completion of study treatment, participants are followed up at 30 days then every 12 weeks.

Pembrolizumab in Treating Participants With Metastatic, Recurrent or Locally Advanced Cancer and Genomic Instability

A Basket Trial of Pembrolizumab in Patients With Advanced Solid Tumors and Genomic Instability

Will calculate the 95% confidence intervals (CI?s) to assess precision of expected response rate of pembrolizumab in treating patients with specified mutant tumors.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase Ib Study of Alpelisib With Cisplatin in Patients With HPV+ Solid Tumor Malignancies	NCT02620839	Solid Tumors	Alpelisib Cisplatin	18 Years -	University of California, San Francisco
Abexinostat in Combination With Pembrolizumab in Patients With Advanced Solid Tumor Malignancies	NCT03590054	Stage III Cutan... Stage IV Cutane... Locally Advance... Locally Advance... Metastatic Head... Metastatic Mali... Metastatic Mela... Metastatic Urot... Non-Small Cell ... Stage IB Lung C... Stage III Cutan... Stage III Lung ... Stage III Urete... Stage IIIA Lung... Stage IIIB Lung... Stage IIIC Lung... Stage IV Cutane... Stage IV Lung C... Stage IV Ureter... Stage IVA Lung ... Stage IVB Lung ...	Abexinostat Pembrolizumab	18 Years -	University of California, San Francisco
Phase Ib Study of Alpelisib With Cisplatin in Patients With HPV+ Solid Tumor Malignancies	NCT02620839	Solid Tumors	Alpelisib Cisplatin	18 Years -	University of California, San Francisco
Pembrolizumab in Treating Participants With Metastatic, Recurrent or Locally Advanced Cancer and Genomic Instability	NCT03428802	BRCA1 Gene Muta... BRCA2 Gene Muta... Locally Advance... Metastatic Mali... POLD1 Gene Muta... POLE Gene Mutat... Recurrent Malig... Recurrent Ovari... Stage III Breas... Stage III Ovari... Stage IIIA Brea... Stage IIIA Ovar... Stage IIIB Brea... Stage IIIB Ovar... Stage IIIC Brea... Stage IIIC Ovar... Stage IV Breast... Stage IV Ovaria... Stage IVA Ovari... Stage IVB Ovari...	Laboratory Biom... Pembrolizumab	18 Years -	Rutgers, The State University of New Jersey

Spots Global Cancer Trial Database for locally advanced solid neoplasm