Olaparib Dose Escalating Trial + Concurrent RT With or Without Cisplatin in Locally Advanced NSCLC

NCT01562210 | Completed Phase 1

• 2 other identifiers: NL35195.031.11N11ORL
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

Phase I dose escalating trial. Primary objective of this study is to define the maximal tolerated dose (MTD)of Olaparib in combination with high dose radiotherapy with or without daily dose Cisplatin in locally advanced NSCLC. Secondary objectives include to define safety profile, determine PK/Pd variables and document preliminary evidence of objective tumor response.

Conditions

NSCLC

Keywords

NSCLC; Olaparib; CCRT

Outcome Measures

Primary Outcomes (1)

• The incidence of dose limiting toxicities (DLTs)

  The incidence of dose limiting toxicities occuring during the DLT evaluation period (from start of study treatment until 3 months after the last radiation day). This endpoint will be used to determine the maximal tolerated dose of Olaparib in combination with radiotherapy with and without low dose Cisplatin.

  from start until 3 months after the last RT day

Secondary Outcomes (7)

• Additional safety variables

  until 5 years after treatment

• Objective tumor response

  until 5 years after treatment

• Locoregional control rate (LRCR)

  at one year

• Progression free survival

  until 5 years after treatment

• Pharmacokinetic variables

  week -1 (baseline) until week 11

Study Arms (1)

Olaparib, radiation +/- Cisplatin

EXPERIMENTAL

Olaparib and radiotherapy with or without Cisplatin

Drug: Olaparib; Drug: Cisplatin; Radiation: Radiation

Interventions

Olaparib DRUG

Olaparib will be given orally BID for 36 days, administrated with a 12 hour interval. Olaparib will start 2 days before RT and will continue for 2 days after the last RT fraction. Olaparib is also given during the non-radiotherapy days but no maintenance treatment is given after radiotherapy is finished. The first cohort will receive Olaparib with a dose of 25mg BID combined with Cisplatin and RT. Thereafter in both with and without cisplatin arms dose escalation will follow to 50mg, 100mg, 200mg, 300mg and 400mg BID.

Also known as: AZD2281

Olaparib, radiation +/- Cisplatin

Cisplatin DRUG

6 mg/m2 (5 days/week), 1-1.5 hr before the irradiation (week 1 to 5), given as a 5-minutes intravenous infusion.

Also known as: L01XA03

Olaparib, radiation +/- Cisplatin

Radiation RADIATION

A total dose of 66 Gy will be given in 24 fractions from week 1 to 5, excluding the weekends.

Olaparib, radiation +/- Cisplatin

Eligibility Criteria

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

You may qualify if:

• ≥18 years of age
• Histologically or cytologically confirmed diagnosis of NSCLC
• Stage II/III non-operable disease, without malignant pleural effusion
• Presence of at least one measurable target lesion
• Acceptable pulmonary function as defined by a Fev1 of ≥30% and a DLCO of ≥ 40% of predicted,
• NYHA I-II functional status
• Expected risk of radiation-induced pulmonary toxicity is modest: MLD ≤ 20 and maximum cord dose 50 Gy
• WHO performance 0-1
• Life expectancy of at least 6 months
• Adequate hematological, renal and hepatic functions
• Hemoglobin ≥ 5.5 mmol/l
• Leucocytes \> 3.0 x 109/l
• Absolute neutrophil count \> 1.5x109/l
• Platelet count \> 100 x 109/l
• Total bilirubin \< 1.5 x UNL

You may not qualify if:

• Concurrent active malignancy other than localized, non-melanoma skin cancer or carcinoma-in-situ of the cervix (unless definitive treatment was completed 5 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.
• Patients, selected for sequential chemoradiotherapy, are excluded if no disease control (all responses except progression) is obtained after induction chemotherapy.
• Prior:
• Ipsilateral radiotherapy to the chest;
• Chemotherapy for other indications than NSCLC within the last 5 years
• History of interstitial pneumonitis (to include diffuse alveolar damage, non-malignant causes of pneumonitis, ARDS, alveolitis, cryptogenic organising pneumonia, obliterative bronchiolitis, non-malignant causes of pulmonary fibrosis, eligibility based on the judgement of the primary investigator), active infection on day of enrolment
• Significant cardiovascular disease as defined by:
• History of congestive heart failure requiring therapy;
• History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry;
• Presence of severe valvular heart disease;
• Presence of a ventricular arrhythmia requiring treatment;
• Uncontrolled hypertension
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial.
• Participation in other trial with investigational drug or treatment modality

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• AstraZeneca: collaborator

Study Sites (1)

Netherlands Cancer Institute - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL)

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Related Publications (2)

• van Werkhoven E, Hinsley S, Frangou E, Holmes J, de Haan R, Hawkins M, Brown S, Love SB. Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples. BMC Med Res Methodol. 2020 Jun 22;20(1):162. doi: 10.1186/s12874-020-01012-z.

  PMID: 32571298 DERIVED

• 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.

  PMID: 31500595 DERIVED

MeSH Terms

Interventions

olaparib; Cisplatin; Radiation

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Physical Phenomena

Study Officials

• Marcel Verheij, MD, PhD

  Antoni van Leeuwenhoekziekenhuis (NKI-AVL)

  PRINCIPAL INVESTIGATOR

• Michel M. van den Heuvel, MD, PhD

  Antoni van Leeuwenhoekziekenhuis (NKI-AVL)

  PRINCIPAL INVESTIGATOR

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: March 22, 2012
• First Posted: March 23, 2012
• Study Start: April 1, 2012
• Primary Completion: May 1, 2019
• Study Completion: March 13, 2020
• Last Updated: March 17, 2020

Record last verified: 2020-03

Locations

NL (1)