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Laryngeal Cancer Stage IIPhase 1NCT02229656

Olaparib and Radiotherapy in Head and Neck Cancer

A Phase 1 study testing radiotherapy and Olaparib in people with Laryngeal Cancer Stage II and Laryngeal Cancer Stage III, run by The Netherlands Cancer Institute at 1 site in Netherlands.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

Accelerated, normofractionated radiotherapy is the treatment of choice in stage II-III laryngeal and oropharyngeal squamous cell carcinoma (SCC). However, twenty to thirty percent of patients with stage II-III laryngeal and HPV negative oropharyngeal SCC develop disease progression, mainly due to lack of locoregional… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
radiotherapy and Olaparib
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
1 siteNetherlands
Study dates
24 Sep 2014to Jan 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥18 years of age
  • Histologically confirmed squamous cell carcinoma of the larynx stage II-III (T2N0M0 or T1-2N1M0 or T3N0-1M0) or histologically confirmed squamous cell carcinoma of the oropharynx stage II-III (T1-2N1M0 or T3N0-1M0)
  • In case of oropharyngeal carcinoma: tumor HPV status negative
  • WHO performance 0-1
  • Life expectancy of at least 6 months
  • Adequate hematological, renal and hepatic functions
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  • Hemoglobin ≥ 6.2 mmol/l
  • Leucocytes 3.0 x 10E9/l
  • Absolute neutrophil count 1.5x10E9/l
  • Platelet count 100 x 10E9/l
  • Total bilirubin ≤ 1.5 x UNL
  • ASAT/ALAT ≤ 2.5 x UNL
  • Creatinine clearance 50 ml/min; measured using a 24-hours urine sample or calculated using the Cockcroft-Gault formula
  • Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 21 days of study treatment. Non-childbearing potential or postmenopausal is defined as:
  • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
  • LH and FSH levels in post menopausal range for women under 50 years of age
  • Radiation-induced oophorectomy with last menses > 1 year ago
  • Chemotherapy-induced menopause with > 1 year interval since last menses
  • Surgical sterilisation (bilateral oophorectomy or hysterectomy)
  • Patients of reproductive potential must agree to practice two effective medically approved contraceptive method during the trial and 3 months afterwards
  • Signed written informed consent.

Who cannot join

  • Patients eligible for concurrent chemoradiotherapy rather than radiotherapy alone
  • Concurrent active malignancy other than localized, non-melanoma skin cancer or carcinoma-in-situ of the cervix (unless definitive treatment was completed 3 years or more before study entry and the patient has remained disease free)
  • Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 3 weeks prior to start of therapy (or a longer period depending on the defined characteristics of the agents used e.g. 6 weeks for mitomycin or nitrosourea). Patients may continue the use of LHRH agonists for cancer; bisphosphonates for bone disease and corticosteroids.
  • Major surgery within two weeks of starting study treatment.
  • Participation in other trial with investigational drug or treatment modality
  • Gastrointestinal disorders that may interfere with absorption of the study drug or patients who are not able to take oral medication.
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  • Tube feeding before the start of treatment.
  • Prior radiotherapy to head \& neck region.
  • Blood transfusion in the four weeks prior to study entry
  • Persistent toxicities (CTC ≥ grade 2) with the exception of alopecia, caused by previous cancer therapy
  • QT-interval >470 msec
  • Significant cardiovascular disease as defined by:
  • History of congestive heart failure defined as NYHA class III
  • History of unstable angina pectoris or myocardial infarction up to 3 months prior to trial entry;
  • Presence of severe valvular heart disease
  • Presence of a ventricular arrhythmia requiring treatment;
  • Uncontrolled hypertension
  • Patients considered a poor medical risk due to:
  • non-malignant systemic disease
  • active, uncontrolled infection requiring parenteral antibiotics
  • a serious, uncontrolled medical disorder; examples include, but are not limited to:
  • uncontrolled major seizure disorder
  • unstable spinal cord compression
  • superior vena cava syndrome
  • extensive bilateral lung disease on HRCT scan
  • any psychiatric disorder that prohibits obtaining informed consent.
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
  • Patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy.
  • Patients with known active hepatic disease (i.e. Hepatitis B or C)
  • Patients with myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear.
  • Concomitant medications:
  • Any previous treatment with a PARP inhibitor, including olaparib
  • Patients receiving the following classes of inhibitors of CYP3A4 (see paragraph 6.4.2 for guidelines and wash out periods)
  • Azole antifungals
  • Macrolide antibiotics
  • Protease inhibitors
  • Breast-feeding women

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

  • The Netherlands Cancer Institute

    Amsterdam, 1066 CX

Other trials in Netherlands

About this study

Official title: Olaparib Dose Escalation Trial in Patients Treated With Radiotherapy for Stage II-III Laryngeal and Stage II-III HPV-negative Oropharyngeal Squamous Cell Carcinoma

Accelerated, normofractionated radiotherapy is the treatment of choice in stage II-III laryngeal and oropharyngeal squamous cell carcinoma (SCC). However, twenty to thirty percent of patients with stage II-III laryngeal and HPV negative oropharyngeal SCC develop disease progression, mainly due to lack of locoregional control. Radiosensitizers such as cisplatin and cetuximab are added to radiotherapy in more advanced stage of head and neck (H\&N) cancer. These radiosensitizers improve loco-regional control and overall survival. Unfortunately, as these radiosensitizers, notably cisplatin, also dose intensify the radiation dose in normal tissues, they also significantly increase toxicity. Adding a more tumor-specific radiosensitizing agent could improve loco-regional control and overall survival without significantly increasing toxicity.

Radiotherapy kills tumor cells by inducing DNA damage. The efficacy of radiotherapy is limited by the ability of tumor cells to repair this DNA damage. Poly(ADP-ribose)polymerase (PARP) is an essential enzyme in base excision repair and single strand break DNA repair, DNA lesions arising from radiation treatment. PARP inhibition and consequently the inhibition of PARP-facilitated DNA repair enhances the anti-tumor activity of radiotherapy, as shown in preclinical studies including head and neck xenograft studies. This radiosensitization is thought to be proliferation dependent and is more pronounced in homologous recombination (HR) deficient cells, providing an opportunity for tumor specific targeting. Genetic analyses suggest that HR deficiency is commonly found in H\&N SCC: ATM loss has been reported in 60% of human H\&N SCC biopsies and FANC-F defects were reported in 15-21% of human H\&N SCC biopsies and cell lines.

Read more

The efficacy of radiotherapy is also limited by tumor hypoxia, as tumor hypoxia results in radioresistance. Some PARP inhibiting compounds increase tumor perfusion in xenograft models, thereby reducing hypoxia and specifically sensitizing tumor cells to radiotherapy. Hypoxia is commonly found in H\&N SCC and a high pre-treatment hypoxic fraction in H\&N SCC tumors is associated with worse outcome. The high prevalence of both hypoxia and HR deficiencies in H\&N SCC support the concept of tumor-specific radiosensitization by PARP inhibition in head and neck cancer patients.

Olaparib is a potent PARP inhibitor developed as an anti-cancer drug for HR defected tumors and as a dose intensifier for chemo- and radiotherapy. In humans, olaparib has a low toxicity profile as a single agent, with increasing bone marrow toxicity when combined with chemotherapy. The combination of olaparib and radiotherapy for H\&N SCC is expected to improve locoregional control and thereby overall survival. However, this combination treatment has never been tested in humans before. The purpose of this study is to determine the safety and tolerability of radiotherapy for stage II-III laryngeal and stage II-III HPV-negative oropharyngeal SCC with concurrent olaparib.

Being tested
radiotherapy, Olaparib
Keywords
olaparib, radiotherapy, Laryngeal SCC, oropharyngeal SCC
Medical subject headings
Laryngeal Neoplasms, Carcinoma, Squamous Cell, Head and Neck Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • radiotherapyRadiation

    Primary tumor and lymph nodes will receive 35 fractions of 2 Gy resulting in a total dose of 70 Gy. Elective fields will receive 35 fractions of 1.55 Gy resulting in a total dose of 54.25 Gy in case a SIB technique is used, or 23 fractions of 2 Gy resulting in a total dose of 46 Gy in case a sequential boost technique is used. The higher total prescribed physical dose to the elective fields in a SIB technique based RT plan compensates for the lower dose per fraction and results in an equal biological effective dose when compared with a sequential boost technique.

  • OlaparibDrug

    Also called AZD2281, KU-0059436

    The pre-defined dose levels of olaparib are 25mg QD, 25, 50, 100, 200, and 300 mg BID

Study groups in NCT02229656
Study groupRoleWhat they receive
radiotherapy and olaparibExperimentalRadiotherapy will be given with accelerated fractionation following the DAHANCA schedule Olaparib: dose escalation
Receives: Radiation: radiotherapy; Drug: Olaparib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The incidence of dose limiting toxicities

    • Blood transfusion dependency as judged by the PI, unless the patient has progressive disease
    • Development of MDS/AML
    • Grade ≥ 4 dysphagia
    • Grade ≥ 3 hemorrhage, aspiration, skin atrophy, trismus, osteoradionecrosis, radiation dermatitis, pneumonitis
    • Grade ≥ 2 fistula, myelitis
    • Grade ≥ 2 mucosal ulcer present ≥ 6 months after end of treatment
    • Fibrosis limiting joint or orifice movement (e.g. mouth) and/or limiting self care ADL
    • Only in patients with oropharynx SCC: grade ≥ 3 larynx stenosis
    • Any other (non-)hematological toxicity, which in the judgment of the Investigator is viewed as DLT; excluding fatigue

    Measured: 1 year

Secondary outcomes (2)

  1. acute toxicity

    severity, duration and relation with treatment of all adverse events according to CTCAE version 4.03

    Measured: until 3 months after treatment

  2. late toxicity

    severity, duration and relation with treatment of possibly, probably or definitely related adverse events according to CTCAE version 4.03

    Measured: 3 months until 2 year after treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Sep 2014 (estimated)
  2. Study start24 Sep 2014
  3. Primary completion14 Jan 2020
  4. Study completionJan 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02229656
Sponsor's protocol ID
N13ORH
Other IDs
2011-002963-79
Status last verified
Nov 2023
First submitted
28 Aug 2014
Last updated
7 Nov 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • de Haan R, van Werkhoven E, van den Heuvel MM, Peulen HMU, Sonke GS, Elkhuizen P, van den Brekel MWM, Tesselaar MET, Vens C, Schellens JHM, van Triest B, Verheij M. Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib. BMC Cancer. 2019 Sep 10;19(1):901. doi: 10.1186/s12885-019-6121-3.

    PubMed 31500595

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing radiotherapy and Olaparib in people with Laryngeal Cancer Stage II and Laryngeal Cancer Stage III, run by The Netherlands Cancer Institute at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 7 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The incidence of dose limiting toxicities (time frame: 1 year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02229656, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Nov 2023.

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