Targeting the Tumor Microenvironment in R/M SCCHN

NCT03844763 | Unknown Phase 1

• 1 other identifier: 2017-000353-39
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 2

Brief Summary

Phase I - II trial of the combination of cyclophosphamide, RT, and Avelumab in relapsed/metastatic HNSCC (R/M-HNC). Patients pretreated with at least one line therapy containing platinum, fluorouracil, and Cetuximab. Treatment consists of metronomic cyclophosphamide 50 mg daily without drug free break, avelumab 10 mg/kg d1 and 15 q 29, and radiotherapy in one or three daily fractions up to 8 Gy maximum dose, starting at day 8. The aim of the study is to reverse tumor immune-escape by:

1. 1.Provide a self-vaccination with radiotherapy
2. 2.Inhibit the immunosuppressive CD4+ CD25+ FoxP3+ Treg cells with metronomic cyclophosphamide
3. 3.Reactivate the effector T cell by the inhibition of PD-1 - PD-L1 axis with avelumab.

Conditions

Head and Neck Cancer

Keywords

Immunotherapy; Avelumab; Head and neck cancer; Radiotherapy; Cyclophosphamide

Outcome Measures

Primary Outcomes (2)

• Adverse Events (AEs)

  Assessment of the safety profile of the association of avelumab and metronomic cyclophosphamide will be graded using the common toxicity criteria and adverse events (NCI CTC-AE v 4.0).Grade refers to the severity of the AE. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. Each adverse event will be reported as the maximum level observed in each patient.

  4 months

• Objective response rate

  Objective response is defined as complete response or partial response as defined as per RECIST evaluation criteria v1.1 (RECIST 1.1).

  2-4 months

Secondary Outcomes (5)

• Toxicity of the combination

  1 month

• Progression Free Survival (PFS)

  54 months

• Quality of Life (QoL)

  2 months

• H&N specific Quality of Life (QoL)

  2 months

• Overall Survival (OS)

  54 months

Study Arms (1)

Phase I - II trial of CTX, RT, Avelumab

EXPERIMENTAL

CTX: 50 mg Daily untill PD or major toxicity; Avelumab: 10 mg/kg every 2 weeks, untill PD or major toxicity; RT: 8 Gy single shot day 8.

Drug: Avelumab; Drug: CTX; Radiation: RT

Interventions

Avelumab DRUG

Avelumab: 10 mg/kg every 2 weeks, untill PD or major toxicity

Also known as: anti PD-L1

Phase I - II trial of CTX, RT, Avelumab

CTX DRUG

CTX: 50 mg Daily untill PD or major toxicity

Also known as: cyclophosphamide

Phase I - II trial of CTX, RT, Avelumab

RT RADIATION

RT: 8 Gy single shot day 8

Also known as: Radiotherapy

Phase I - II trial of CTX, RT, Avelumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be willing and able to provide written informed consent for the trial. The subject may also provide consent for the translational study.
• Be 18 years of age on day of signing informed consent.
• ECOG Performance Status 0-2.
• Have histologically or cytologically-confirmed recurrent or metastatic (disseminated) head and neck squamous cell carcinoma
• Have a disease progression after treatment with at least one line of therapy including at least Cisplatin, Fluorouracil and Cetuximab for recurrent (disease not amenable to curative treatment)/metastatic disease.
• Measurable disease by RECIST criteria.
• At least one metastatic site suitable for irradiation
• Life expectancy \> 3 months.
• Adequate bone marrow function: neutrophils 1.5 x 109/L, platelets 100 x 109/L, hemoglobin 9 g/dL.
• Adequate liver function: AST and ALT levels 2.5 × ULN; bilirubin 1.5 x ULN.
• Adequate renal function: creatinine clearance 30 mL/min (Cockroft-Gault).
• Fertil men must be using adequate contraceptive measures throughout the study period if their partner are women of childbearing potential.
• If of childbearing potential, women must use effective contraceptive method (Pearl Index \< 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant, transdermal patch, a combination of two barrier methods (condom and diaphragm), sterilisation, sexual abstinence) for the study duration and for at least 6 months after last avelumab treatment administration if the risk of conception exists.

You may not qualify if:

• History of malignant disease (with the exception of non-melanoma skin tumours and/or in situ cervical cancer) in the preceding five years.
• Brain metastases.
• Autoimmune disorders. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
• Allergic disorders.
• Cyclophosphamide treatment contraindications:
• Cystitis.
• Urinary Obstruction.
• Inadequate bone marrow function: WBC \<2900 mm3 and/or HCT \<30% and/or platelets count \<90000 mm3.
• Active infections.
• Pregnancy or breast feeding.
• Prior treatment with inhibitors of the PD-L1 - PD - 1 axis or inhibitors of CTLA-4 (immune check point inhibitors)
• Previous HBV or HCV infections.
• Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• Any active infection requiring specific treatment (Antibiotics, antimicotic, antiviral).
• Radiotherapy within 6 weeks before enrolment

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead

Study Sites (2)

AO Santa Croce e Carle di Cuneo

Cuneo, Italia/cuneo, 12100, Italy

NOT YET RECRUITING

Azienda Ospedaliera S. Croce E Carle Di Cuneo - Cuneo (Cn) Oncologia Medica

Cuneo, 12100, Italy

RECRUITING

Related Publications (7)

• Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331.

  PMID: 18173375 BACKGROUND

• Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013 Jul;94(1):25-39. doi: 10.1189/jlb.1212621. Epub 2013 Apr 26.

  PMID: 23625198 BACKGROUND

• Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009 Dec 21;206(13):3015-29. doi: 10.1084/jem.20090847. Epub 2009 Dec 14.

  PMID: 20008522 BACKGROUND

• Li X, Kostareli E, Suffner J, Garbi N, Hammerling GJ. Efficient Treg depletion induces T-cell infiltration and rejection of large tumors. Eur J Immunol. 2010 Dec;40(12):3325-35. doi: 10.1002/eji.201041093.

  PMID: 21072887 BACKGROUND

• Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007 May;56(5):641-8. doi: 10.1007/s00262-006-0225-8. Epub 2006 Sep 8.

  PMID: 16960692 BACKGROUND

• Haikerwal SJ, Hagekyriakou J, MacManus M, Martin OA, Haynes NM. Building immunity to cancer with radiation therapy. Cancer Lett. 2015 Nov 28;368(2):198-208. doi: 10.1016/j.canlet.2015.01.009. Epub 2015 Jan 12.

  PMID: 25592036 BACKGROUND

• Chandra RA, Wilhite TJ, Balboni TA, Alexander BM, Spektor A, Ott PA, Ng AK, Hodi FS, Schoenfeld JD. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology. 2015 May 28;4(11):e1046028. doi: 10.1080/2162402X.2015.1046028. eCollection 2015 Nov.

  PMID: 26451318 BACKGROUND

MeSH Terms

Conditions

Head and Neck Neoplasms

Interventions

avelumab; Cyclophosphamide; Radiotherapy

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Therapeutics

Study Officials

• MARCO C MERLANO, DR

  AO S CROCE E CARLE DI CUNEO

  PRINCIPAL INVESTIGATOR

Central Study Contacts

MARCO C MERLANO, DR

CONTACT

+390171616739; MCMERLANO@GMAIL.COM

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 11, 2019
• First Posted: February 18, 2019
• Study Start: January 7, 2019
• Primary Completion: June 30, 2024
• Study Completion: June 30, 2024
• Last Updated: March 3, 2020

Record last verified: 2020-03

Locations

IT (2)