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Nivolumab

Cyclophosphamide

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Antineoplastic Agents, Alkylating

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Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

patient with progressive/relapsed solid tumors who failed first line therapy

treatment with IV Nivolumab 3mg/kg every 2 weeks . after a month-addition of low dose cyclophosphamide at a starting dose of 50 mg/kg/day x7 days every 14 days with dose adaptation based on level of Tregulatory cells on follow up immunophenotype.

Nivolumab,low dose cyclophosphamide

Iris Fried, MD

patients with progressive/relapsed solid tumors who failed first line therapy , will be treated biweekly with the anti PD1- Nivolumab. at least one month after treatment initiation low dose cyclophosphamide will be started .

patients on trial will submit tissue and blood tests for whole exome an immune genomic signature. patients will also undergo repeated immunophenotype as part of follow up.

Programmed cell death 1 (PD-1) is an inhibitory receptor that prevents immune activation. PD-1 blockade can mediate reactivation of immune mediated tumor killing leading to tumor regression . Another mechanism of tumor associated immune inactivation is elevation of rates of T regulatory cells. This process may be prevented by treatment with low dose cyclophosphamide.

Objective:

This study will evaluate safety and tolerability of the anti PD1 antibody Nivolumab combined with other immunomodulating treatments, in pediatric patients with relapsed/progressive solid tumors

Method:

Patients will be treated with IV Nivolumab 3mg/kg over 60 minutes on day 1 and 15 of each cycle of 28 days.

1. Dose finding phase:

   1. Six patients will be accrued for the first cohort and treated for 1 month
   2. If an adverse event \>grade 2 will occur in\>2 patients, study medication dose will be reduced by 25% and another cohort of 6 patients will be accrued on the reduced dose.
   3. Dose finding cohorts will be accrued until determination of a dose with allowed DLT
2. Expansion phase

   1. Following dose determination patients will be accrued, to the final number of 30 patients
   2. Cyclophosphamide at the dose of 50 mg/dayx7days every 14 days (one week on one week off ) will be started . immunophenotype will be done every 28 days and dose of cyclophosphamide will be elevated by 25mg /day every month until highest ratio of CD8/CD25FOXP3 cells will be reached for every child
   3. All patients will be treated for 1 year or until imaging proven disease progression.
3. Required follow up

   1. All patients will undergo tumor bed imaging (CT/MRI-based on tumor location) with metastatic evaluation (according to standar follow up) every 4 months
   2. Tumor response will be measured based on RECIST criteria
   3. Toxicity assessment will be done according to the CTCAE v. 4.03

c. Collateral studies:

1. Immunohistochemical analysis for PD1 and PDL1 will be done on pretreatment paraffin embedded tissue to estimate it's ability to predict response.
2. Immune profile of peripheral blood lymphocytes including CD3+, CD4+, CD8+ FOX P3+ cells and it's correlation to objective response to therapy.
3. Exome sequencing of the tumor and peripheral blood will be done for every patient.

Exome will be evaluated for driver mutations and immunologic genomic signature.

Nivolumab in Relapsed Pediatric Solid Tumors

A Phase I/II Clinical Trial of Nivolumab in Progressive/Relapsed Pediatric Solid Tumors

Rate of patients with stable disease/tumor response at 6 months

Rate of patients alive at 6 months and 12 months

correlation between levels of PD1 receptor expression in the tumor and genomic signature with response

Hadassah Medical Organization

Micronutrients

Anti-Infective Agents

Hematinics

Vitamins

Antibodies

Gemcitabine

Trastuzumab

Paclitaxel

Carboplatin

Irinotecan

Cetuximab

Leucovorin

Fluorouracil

Levoleucovorin

Everolimus

Albumin-Bound Paclitaxel

Cisplatin

Epirubicin

Sirolimus

Folic Acid

Immunoglobulins

Mitogens

Erlotinib Hydrochloride

Temsirolimus

MTOR Inhibitors

Vitamin B Complex

Antimetabolites

Topoisomerase I Inhibitors

Enzyme Inhibitors

Protein Kinase Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antidotes

Protective Agents

Trace Elements

Folinic Acid

Folate

Vitamin B9

Participants with colorectal adenocarcinoma receive FOLFIRI (Irinotecan 180 mg/m\^2+ folinic acid 400 mg/m\^2+ 5-fluorouracil \[5-FU\] 400 mg/m\^2 bolus followed by 2400 mg/m\^2 intravenous \[IV\] infusion over 46 hours) (± cetuximab initial dose of 400 mg/m\^2 IV followed by once-weekly doses of 250 mg/m\^2 IV) PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 2-week cycle.

Participants with non-small cell lung cancer receive carboplatin administered at an area under the curve (AUC) of 6 mg/mL/min IV PLUS paclitaxel 225 mg/m\^2 IV PLUS robatumumab 15 mg/kg IV on Day 1 of each 3-week cycle.

Participants with gastric adenocarcinoma receive epirubicin 50 mg/m\^2 IV PLUS cisplatin 60 mg/m\^2 IV PLUS 5-FU 200 mg/m\^2/day administered via a 21-week continuous IV infusion PLUS robatumumab 15 mg/kg IV on Day 1 of each 3-week cycle.

Participants with human epidermal growth factor receptor 2 positive (Her2+) breast cancer receive trastuzumab 4 mg/kg IV once every week PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 4-week cycle.

Participants with renal cell cancer receive mammalian target of rapamycin (mTor) inhibitor (everolimus) 10 mg orally once per day PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 4-week cycle.

Participants with pancreatic adenocarcinoma receive gemcitabine 1000 mg/m\^2 IV on Days 1, 8, 15, 22, 29, 36, and 43 in Cycle 1 and on Days 1, 8 and 15 in subsequent cycles (± erlotinib 100 mg per day orally) PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 4-week cycle. (Cycle 1 is 8 weeks.)

In Part 1, robatumumab was to be administered at 10 mg/kg, 15 mg/kg (for Regimens B and C), or 20 mg/kg together with the assigned standard treatment. For Part 2, robatumumab was to be administered at the dose selected during Part 1, based upon the maximum tolerated dose (MTD) or maximum administered dose (MAD), pharmacokinetic (PK) and pharmacodynamic (PD) data.

Robatumumab

5-FU

Erlotinib

Medical Director

This is a Phase 1B/2, non-randomized, dose-escalation, multicenter, open-label study designed to evaluate the safety and tolerability of robatumumab (SCH 717454, MK-7454) in combination with standard treatment in participants with advanced solid tumors to be conducted in conformance with Good Clinical Practices.

Six different treatment regimens will be investigated in combination with robatumumab.

The study will be divided into two parts. Part 1 will consist of initial safety evaluation and dose-finding of robatumumab in combination with each treatment regimen. Part 2 will consist of an expansion of each robatumumab regimen at a newly established dose level, to better define safety, tolerability, and initial efficacy in specific target populations.

Study of Robatumumab (SCH 717454, MK-7454) in Combination With Different Treatment Regimens in Participants With Advanced Solid Tumors (P04722, MK-7454-004)

A Dose-Escalation Study to Evaluate the Safety and Tolerability of SCH 717454 in Combination With Different Treatment Regimens in Subjects With Advanced Solid Tumors (Phase 1B/2; Protocol No. P04722)

https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Overall best response was determined by RECIST criteria. Types of overall response could be: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), Not Assessable (NA) or Incomplete Response/Stable Disease (IR/SD).

An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to this study drug. AEs may include the onset of new illness and the exacerbation of pre-existing conditions.

Merck Sharp & Dohme LLC

The All Treated Set consisted of all participants who received ≥1 dose of study drug.

Participants with colorectal adenocarcinoma receive FOLFIRI (Irinotecan 180 mg/m\^2+ folinic acid 400 mg/m\^2+ 5-FU 400 mg/m\^2 bolus followed by 2400 mg/m\^2 IV infusion over 46 hours) (± cetuximab initial dose of 400 mg/m\^2 followed by once-weekly doses of 250 mg/m\^2) PLUS robatumumab 10 mg/kg or 20 mg/kg IV. Each cycle is 2 weeks.

Regimen A: FOLFIRI (+/- Cetuximab) + Robatumumab

Participants with non-small cell lung cancer receive carboplatin administered at an AUC of 6 mg/mL/min IV PLUS paclitaxel 225 mg/m\^2 IV PLUS robatumumab 15 mg/kg IV on Day 1 of each 3-week cycle.

Regimen B: Carboplatin + Paclitaxel + Robatumumab

Participants with Her2+ breast cancer receive trastuzumab 4 mg/kg IV once every week PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 4-week cycle.

Regimen D: Trastuzumab + Robatumumab

Participants with renal cell cancer receive mTor inhibitor (everolimus) 10 mg orally once per day PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 4-week cycle.

Regimen E: mTor Inhibitor (Everolimus) + Robatumumab

Participants with pancreatic adenocarcinoma receive gemcitabine 1000 mg/m\^2 on Days 1, 8, 15, 22, 29, 36, and 43 (± erlotinib 100 mg per day) PLUS robatumumab 10 mg/kg or 20 mg/kg IV. Each cycle is 8 weeks.

Regimen F: Gemcitabine (+/- Erlotinib) + Robatumumab

Participants with colorectal adenocarcinoma receive FOLFIRI (Irinotecan 180 mg/m\^2+ folinic acid 400 mg/m\^2+ 5-FU 400 mg/m\^2 bolus followed by 2400 mg/m\^2 IV infusion over 46 hours) (± cetuximab initial dose of 400 mg/m\^2 IV followed by once-weekly doses of 250 mg/m\^2 IV) PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 2-week cycle.

Regimen A: FOLFIRI (± Cetuximab) + Robatumumab

Regimen C: Epirubicin + Cisplatin + 5-FU + Robatumumab

Regimen F: Gemcitabine (± Erlotinib) + Robatumumab

Total

Age, Continuous

Sex: Female, Male

Senior Vice President, Global Clinical Development

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Not Assessable (NA)

Incomplete Response/Stable Disease (IR/SD)

The All Treated Set (efficacy) consisted of all participants who received ≥1 dose of study drug and were evaluable for this outcome measure.

Part 2: Number of Participants With Each Type of Response Evaluation Criteria in Solid Tumors (RECIST)-Determined Overall Best Response

The All Treated Set (safety) consisted of all participants who received ≥1 dose of study drug.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Nivolumab in Relapsed Pediatric Solid Tumors	NCT02901145	Antibodies, Neo...	Nivolumab,low d...	1 Year - 21 Years	Hadassah Medical Organization
Study of Robatumumab (SCH 717454, MK-7454) in Combination With Different Treatment Regimens in Participants With Advanced Solid Tumors (P04722, MK-7454-004)	NCT00954512	Neoplasms	Carboplatin Epirubicin Trastuzumab Everolimus Gemcitabine Robatumumab Cetuximab Paclitaxel Cisplatin 5-FU Erlotinib Irinotecan Folinic Acid	18 Years -	Merck Sharp & Dohme LLC

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