Olaparib and Radiotherapy in Head and Neck Cancer

Sponsor
The Netherlands Cancer Institute
Study ID
NCT02229656
Phase
PHASE1
Status
Unknown

Conditions

  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms
  • Laryngeal Cancer Stage II
  • Laryngeal Cancer Stage III

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • radiotherapy — RADIATION
    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.
  • Olaparib — DRUG
    The pre-defined dose levels of olaparib are 25mg QD, 25, 50, 100, 200, and 300 mg BID

Study Details

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. 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.

Key Dates

Start date
Sep 24, 2014
Status verified
Nov 2023
Primary completion
Jan 14, 2020
Completion
Jan 31, 2024

Study Design

Enrollment
12 participants (actual)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: radiotherapy and olaparib
    Radiotherapy will be given with accelerated fractionation following the DAHANCA schedule Olaparib: dose escalation

Primary Outcome Measure

The incidence of dose limiting toxicities [ Time Frame: 1 year ]

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