UPSTREAM: Biomarker-based Study in R/M SCCHN

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Recruiting

CT.gov ID

NCT03088059

Collaborator

(none)

340

Enrollment

Locations

Arms

96.5

Anticipated Duration (Months)

9.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a biomarker-driven trial that will enroll patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing after first-line platinum-based chemotherapy. Based on potential biomarkers and molecular alterations identified in the biopsy from the central platform, patients will be allocated in different cohorts. There will be biomarker-positive patient cohorts and immunotherapy cohorts.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Squamous Cell of Head and Neck	Drug: Afatinib Drug: Palbociclib Drug: standard of care Drug: IPH2201 Drug: Durvalumab Drug: Niraparib Drug: INCAGN01876	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

340 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Pilot Study of Personalized Biomarker-based Treatment Strategy or Immunotherapy in Patients With Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck

Actual Study Start Date :

Nov 16, 2017

Anticipated Primary Completion Date :

Jun 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Patient Cohort B1 Patients who are p16 negative and have an EGFR amplification/mutation or PTEN high or HER2 mutation/amplification will be randomized between afatinib or the standard of care (Methotrexate, Paclitaxel, Docetaxel, Carboplatin, 5-Fluorouracil, Bleomycine, Gemcitabine, Mitomycine or Best supportive care).	Drug: Afatinib Afatinib 40 mg given orally, once daily, 1 cycle is 28 days Drug: standard of care Methotrexate, Paclitaxel, Docetaxel, Carboplatin, 5-Fluorouracil, Bleomycine, Gemcitabine, Mitomycine or Best supportive care
Experimental: Patient Cohort B2 Patients who are p16 negative and cetuximab naïve will be randomized between afatinib or the standard of care (Methotrexate, Paclitaxel, Docetaxel, Carboplatin, 5-Fluorouracil, Bleomycine, Gemcitabine, Mitomycine or Best supportive care)	Drug: Afatinib Afatinib 40 mg given orally, once daily, 1 cycle is 28 days Drug: standard of care Methotrexate, Paclitaxel, Docetaxel, Carboplatin, 5-Fluorouracil, Bleomycine, Gemcitabine, Mitomycine or Best supportive care
Experimental: Patient Cohort B3 Patients who are p16 negative and have an amplification of CCND1 will be randomized between palbociclib or the standard of care (Methotrexate, Paclitaxel, Docetaxel, Carboplatin, 5-Fluorouracil, Bleomycine, Gemcitabine, Mitomycine or Best supportive care)	Drug: Palbociclib Palbociclib 125 mg given orally, once daily, 1 cycle is 28 days (21 days on treatment, then 7 days off) Drug: standard of care Methotrexate, Paclitaxel, Docetaxel, Carboplatin, 5-Fluorouracil, Bleomycine, Gemcitabine, Mitomycine or Best supportive care
Experimental: Patient Cohort B4 Patients who are p16 negative and 'platinum sensitive' SCCHN will receive niraparib	Drug: Niraparib Niraparib 300 mg given orally, once daily, 1 cycle is 28 days
Experimental: Patient Cohort B5 Patients whith oropharyngeal cancer and which are p16 positive will receive niraparib	Drug: Niraparib Niraparib 300 mg given orally, once daily, 1 cycle is 28 days
Experimental: Patient Cohort I1 Patients who are anti-PD(L)1-naïeve or resistant (primary or secondary resistance) will receive IPH2201 antibody (monalizumab).	Drug: IPH2201 protocol v2.0 and 2.1 : Monalizumab 10mg/kg given intravenously over 60 minutes, once every 14 days, 1 cycle is 14 days protocol v4.0 : Monalizumab 750mg given intravenously over 60 minutes, once every 28 days, 1 cycle is 28 days Other Names: Monalizumab
Experimental: Patient Cohort I2 Patient who are PD(L)1 pretreated will be randomized between monalizumab + durvalumab or the standard of care (Methotrexate, Paclitaxel, Docetaxel, Carboplatin, 5-Fluorouracil, Bleomycine, Gemcitabine, Mitomycine or Best supportive care)	Drug: standard of care Methotrexate, Paclitaxel, Docetaxel, Carboplatin, 5-Fluorouracil, Bleomycine, Gemcitabine, Mitomycine or Best supportive care Drug: IPH2201 protocol v2.0 and 2.1 : Monalizumab 10mg/kg given intravenously over 60 minutes, once every 14 days, 1 cycle is 14 days protocol v4.0 : Monalizumab 750mg given intravenously over 60 minutes, once every 28 days, 1 cycle is 28 days Other Names: Monalizumab Drug: Durvalumab Durvalumab 1500mg given intravenously over 60 minutes, once every 28 days, 1 cycle is 28 days
Experimental: Patient Cohort I3 Patient who are progressing prior PD(L)1 after having received at least 2 months of anti-PD(L)-1 will receive INCAGN01876.	Drug: INCAGN01876 INCAGN01876 300 mg given intravenously over 30 minutes, once every 14 days, 1 cycle is 28 days

Outcome Measures

Primary Outcome Measures

Progression Free Survival Rate (PFSR) at week 16 [The Progression Free Survival Rate (PFSR) analysis will be performed at week 16 for each patient in cohorts 1, 2 and 3.]
Progression Free Survival Rate (PFSR) at week 16 will be assessed as primary endpoint for all patients from cohorts 1, 2 and 3.
Objective response Rate (ORR) at week 16 [Objective response Rate (ORR) at week 16 will be performed at week 16 for each patient in cohort 4.]
Objective response Rate (ORR) during the first 16 weeks of study treatment will be assessed as primary endpoint for all patients from cohort 4-8.

Secondary Outcome Measures

Progression Free Survival (PFS) [54 months after first patient in]
Objective Response Rate [48 months after first patient in]
Objective Response Rate will be measured according to both RECIST 1.1 and iRECIST
Response duration [54 months after first patient in]
Overall Survival (OS) [54 months after first patient in]
Toxicity according CTCAE version 4.03 [54 months after first patient in]
This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, for adverse event reporting.
Percentage of patients included in each patient cohort according the biomarker testing [42 months after first patient in]
The percentage of patients with an evaluable fresh tumor biopsy [42 months after first patient in]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

General Inclusion Criteria:

Histologically confirmed recurrent and/or metastatic SCCHN of the oral cavity, oropharynx, hypopharynx or larynx not amenable to curative treatment.
At least one measurable lesion by MRI or CT-scan according to RECIST 1.1, evaluated within 2 weeks prior to registration. Such lesion must not have been previously irradiated; if the measurable lesion(s) have been irradiated, clear progression must be documented.
Progressive disease after first line platinum-based chemotherapy with or without cetuximab given as palliative treatment or progressive disease within 1 year if platinum-based chemotherapy was given as a part of the multimodal curative treatment. Patients pre-treated with anti-PD1/anti-PDL1 are allowed.
ECOG performance status 0 -1 with a life expectancy of at least 12 weeks.
Tumor core biopsy from any accessible tumor at the recurrent or metastatic site available for central testing.
Patients must have adequate organ function, evaluated within 14 days prior to cohort allocation:
Hemoglobin ≥ 9 g/100 ml,
Neutrophils ≥ 1,500/mm3,
Platelets ≥ 100,000/mm3,
Total bilirubin <1.5 times the upper limit of normal (ULN) (< 3 times the upper limit of normal for Gilbert's disease),
Serum ALT and AST ≤ 2.5 x ULN,
Adequate renal function measured by:
Estimated creatinine clearance ≥45ml using Cockcroft and Gault formula or Creatinine ≤ 1.5 ULN
International Normalized Ratio (INR) or Prothrombin Time (PT) must be within the normal ranges as per institution's standard. A window of 5% is allowed.
Patients receiving anticoagulant therapy are allowed to participate as long as the PT/INR values are within the expected target range of their current dose.
Clinically normal cardiac function based on -left ventricular ejection fraction (≥ 50%) as assessed either by multi-gated acquisition scan or cardiac ultrasound and 12 lead ECG without clinically relevant abnormalities.
Patients ≥ 18 years old and must be able to give written informed consent.
Patients ≥ 70 years old must undergo the G8 screening.
Women of child-bearing potential must have a negative pregnancy test (serum or urine within the 72 hours prior to cohort allocation).
Patients of childbearing / reproductive potential must agree to use highly effective methods of contraception based on the Clinical Trial Facilitation Group (CTFG) guidance as of registration and up to 6 months after the last treatment dose. Highly effective methods can achieve failure rate of less than 1% per year when used consistently and correctly. Such methods include: For Women: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal and transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner and sexual abstinence. For Men: condoms, sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient) and no sperm donations during treatment and up to 6 months after last dose of treatment.
Female subjects who are breast feeding should agree to discontinue nursing prior to the first dose of study treatment and up to 6 months after the last study treatment.
Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

General Exclusion Criteria:

Unresolved and significant toxicity CTCAE version 4.03 grade ≥ 2 from previous anticancer therapy other than alopecia.
History of any of the following cardiovascular conditions within 6 months prior to registration:
myocardial infarction,
severe/unstable angina,
ongoing cardiac dysrhythmias of CTCAE version 4.03 Grade 2 or more,
atrial fibrillation of any grade,
coronary/peripheral artery bypass graft,
symptomatic congestive heart failure according to New York Heart Association (NYHA) Class III or Class IV,
significant active cardiac disease including uncontrolled high blood pressure defined as systolic ≥150 and diastolic ≥100.
cerebrovascular accident including transient ischemic attack
thromboembolic events like symptomatic pulmonary embolism.
Nasopharynx and sino-nasal tumor.
Surgery or investigational drugs or chemotherapy or other anticancer therapy within 3 weeks before cohort allocationor or for investigational drugs, within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter. Participant must have recovered from any surgical procedure. Curative radiation therapy (60-70 Gy) within 6 weeks of cohort allocation. Palliative radiation therapy (e.g. 8 Gy on a painful lesion) will be allowed.
Known untreated and uncontrolled brain metastases or leptomeningeal carcinomatosis.
Known diagnosis of immune deficiency or a positive serology of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected) or pre-existing liver cirrhosis.
Known pre-existing interstitial lung disease (ILD). Bronchoemphysema is not considered as ILD.
Other uncontrolled active illnesses or nonmalignant systemic disease (examples include, but are not limited to active infections requiring antibiotics, bleeding disorders, uncontrolled diabetes, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome …).
Any psychiatric, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Any malignancy (other than SCCHN, non-melanoma skin cancer or localized cervical cancer or localized and presumed cured prostatic cancer or basal cell carcinoma of the skin and carcinoma in situ of the cervix or bladder) within the last 3 years prior to treatment allocation.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ZNA Middelheim	Antwerp	Belgium
2	CHU Saint-Pierre-Site Porte de Hal	Brussels	Belgium	1000
3	Cliniques Universitaires Saint-Luc	Brussel	Belgium
4	Hopitaux Universitaires Bordet-Erasme - Institut Jules Bordet	Brussel	Belgium
5	Grand Hopital de Charleroi - Grand Hôpital de Charleroi - Site Notre Dame	Charleroi	Belgium
6	Universitair Ziekenhuis Antwerpen	Edegem	Belgium
7	Universitair Ziekenhuis Gent	Gent	Belgium
8	Hopital De Jolimont	Haine-Saint-Paul	Belgium
9	AZ Groeninge Kortrijk - Campus Kennedylaan	Kortrijk	Belgium
10	U.Z. Leuven - Campus Gasthuisberg	Leuven	Belgium	3000
11	U.Z. Leuven - Campus Gasthuisberg	Leuven	Belgium
12	GasthuisZusters Antwerpen - Sint-Augustinus	Wilrijk	Belgium
13	CHU Dinant Godinne - UCL Namur	Yvoir	Belgium
14	CHU de Bordeaux - Groupe Hospitalier Saint-André - Hopital Saint-Andre	Bordeaux	France
15	Centre Georges-Francois-Leclerc	Dijon	France
16	Centre Oscar Lambret	Lille	France	59020
17	Institut de Cancerologie de l'Ouest (ICO) - Centre Rene Gauducheau	Nantes	France
18	Centre Antoine Lacassagne	Nice	France
19	Institut Curie	Paris	France
20	Institut de Cancerologie Strasbourg Europe	Strasbourg	France	67200
21	Institut de Cancérologie de Lorraine	Vandoeuvre Les Nancy	France
22	Gustave Roussy	Villejuif	France
23	Azienda Ospedaliera Papa Giovanni XXIII	Bergamo	Italy
24	Azienda Ospedaliero-Universitaria Careggi	Firenze	Italy	50134
25	Azienda Ospedaliero-Universitaria Careggi	Firenze	Italy
26	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Italy
27	Ospedale San Paolo	Milano	Italy
28	IRCCS - Fondazione G. Pascale	Napoli	Italy	80131
29	Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"	Napoli	Italy
30	University Hospitals Birmingham NHS Foundation Trust (UHB) - UHB-Queen Elisabeth Medical Centre	Birmingham	United Kingdom
31	NHS Lothian - Western General Hospital	Edinburgh	United Kingdom	EH4 2XU
32	NHS Lothian - Western General Hospital	Edinburgh	United Kingdom
33	NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital	Glasgow	United Kingdom
34	Guy's and St Thomas' NHS - Guy s and St Thomas' NHS - Guy's Hospital	London	United Kingdom
35	Oxford University Hospitals NHS Trust - Churchill Hospital	Oxford	United Kingdom
36	Sheffield Teaching Hospitals NHS Foundation Trust - Weston Park Hospital	Sheffield	United Kingdom