Neoplasms

All Conditions

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Cisplatin

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Enzyme Inhibitors

The participants will receive neoadjuvant and adjuvant pembrolizumab and olaparib combination plus standard of care (chemoradiation therapy) as defined in the protocol.

In the induction phase, participants will receive a single intravenous infusion of pembrolizumab 400 mg prior to chemoradiotherapy. In the Maintenance Phase, participants will receive pembrolizumab 400 mg every 42 days for 8 cycles.

In the induction phase, participants will receive daily oral olaparib 150 mg two times a day for 3 weeks prior to chemoradiotherapy. In the Maintenance Phase, participants will receive daily olaparib 150 mg two times a day for up to 48 weeks.

In the chemoradiation phase, participants will receive weekly intravenous cisplatin infusion, 40 mg/m2 over 7 weeks.

In the chemoradiation phase, standard of care radiation therapy and chemotherapy will be administered, for a total of 7 weeks. Radiation therapy is done on daily basis (excluding weekends), and chemotherapy therapy will involve cisplatin infusion once weekly.

In the chemoradiation phase, participants will receive 70 Gray external beam radiotherapy, at 2 Gray/fraction dose, 35 fractions, delivered once a day, on weekdays, using Intensity Modulated Radiotherapy Treatments or proton radiotherapy techniques, over 7 weeks.

IMRT (intensity modulated radiation therapy)

Lori Stravers

Leah Randolph

Jennifer Stacy

Rebecca Redman

Jonathan Jackson

Patricia Brock

Siddharth Sheth

Madison Avinger

Kendall Preston

John Kaczmar, MD

Siddharth Sheth, DO MPH

The purpose of this research study is to evaluate the effectiveness of using a combination of pembrolizumab and olaparib when given before and after standard chemoradiation therapy in treating locally advanced head and neck squamous cell carcinoma. Pembrolizumab and olaparib are drugs that are approved for head and neck cancer treatment. However, FDA has not approved the use of these two drugs together in treating head and neck cancer.

Treatment outcomes are poor for patients with locally advance human papilloma virus (HPV) negative and high-risk HPV positive head and neck squamous cell carcinoma (HNSCC). One standard of care (SOC) for HNSCC is definitive chemoradiotherapy (CRT). This study will evaluate the safety and efficacy of the addition of pembrolizumab, an anti-programmed death-1 (PD1) inhibitor, and olaparib, a Polyadenosine 5'diphosphoribose polymerization (PARP) inhibitor, before and after SOC CRT, which will be delivered in 70 Gray in 35 fractions with concurrent weekly cisplatin 40 mg/m2 over 7 weeks.

Treatment will be offered in three sequential phases. In the induction phase, participants will receive one infusion of pembrolizumab and will take olaparib tablets for a total of 21 days. In the chemoradiation phase, radiation therapy will administered daily (excluding weekends) and cisplatin infusion will be given weekly. In the maintenance phase, pembrolizumab infusion will be done once every 6 weeks in additional to twice daily olaparib tablets for up to 8 treatment cycles that are 42-days per cycle.

Pembrolizumab Plus Olaparib in LA-HNSCC

A Phase II Trial of Induction and Maintenance Pembrolizumab and Olaparib in Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)

One Year PFS will be defined as the period from the date of treatment start until disease progression or death (whichever occurs first) up to one year. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of progression. Progression will be evaluated by RECIST v1.1

RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Overall survival will be defined as the period from the date of treatment start until death of any cause. Subjects who have not had an event will be censored at the date of last assessment documenting the subject was alive.

Two Year PFS will be defined as the period from the date of treatment start until disease progression or death (whichever occurs first) up to two year. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of progression. Progression will be evaluated by RECIST v1.1

RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Induction therapy related delays in chemoradiation therapy (CRT) will be defined type and associated grade of toxicity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. criteria and days of delay to start CRT due to induction one cycle of induction pembrolizumab and olaparib.

Toxicities related to maintenance therapy associated with pembrolizumab and olaparib will be classified and graded according to NCI-CTCAE v5.0.

The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

Induction pembrolizumab and olaparib related toxicity will be defined using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in subjects receiving one cycle of pembrolizumab and olaparib.

Maintenance therapy-related toxicities using patient-reported outcomes (PRO-CTCAE) in subjects who received induction pembrolizumab with olaparib, followed by definitive treatment with concurrent cisplatin-radiotherapy and maintenance pembrolizumab and olaparib.

One-year locoregional control will be defined as the period from the start of treatment until recurrence at primary site or nodal site (whichever occurs first) as defined by RECIST 1.1

DMFS will be defined as the period from the date of treatment start until distant metastasis or death (whichever occurs first) as defined by RECIST 1.1. Subjects who have not had an event will be censored at the date of last disease assessment documenting the subject was free of distant metastasis.

To correlate combined positive score (CPS) with one-year PFS, quality of life scores will be summarized using descriptive statistics like mean, sd, median, range, in participants who received induction pembrolizumab with olaparib, followed by definitive treatment with concurrent cisplatin-radiotherapy and maintenance pembrolizumab and olaparib.

Head and Neck Cancer Associated PRO will be evaluated using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Head and Neck Module (QLQ-H\&N35).

EORTC QLQ-H\&N35 has 35 questions assessing symptoms and side effects of treatment, social function and body image/sexuality. Most questions used 4 point scale (1 'Not at all' to 4 'Very much'); several single item questions were just coded as no=1, yes=2. The scores transformed and analyzed on a 0 - 100 scale. High scores indicate more problems.

General Cancer Associated PRO will be evaluated using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30).

The EORTC QLQ-C30 has 30 questions, 9 multi-items: 5 functional, 9 symptoms and a global health and quality-of-life. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'); 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). The scores transformed and analyzed on a 0 - 100 scale. A higher score=better.

Merck Sharp & Dohme LLC

UNC Lineberger Comprehensive Cancer Center

Digestive System Diseases

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Pharmaceutical Solutions

Micronutrients

Hematinics

Vitamins

Capecitabine

Leucovorin

Fluorouracil

Oxaliplatin

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Folate

Vitamin B9

Patients will receive IMRT along with capecitabine. External radiotherapy will be based on contouring guidelines from the RTOG atlas and Radiation Therapy Oncology Group (RTOG 0822) with some modifications

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus

Cycle length: 14 days (2 weeks)

Duration of treatment: 12 cycles

Then: Surgical Resection

Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus

Cycle length: 14 days (2 weeks)

Duration of treatment: 12 cycles

Then: Surgical Resection

Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Endo-HDR (if randomized to this arm)

Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy

capecitabine and IMRT (if randomized to this arm)

Patients will receive IMRT along with capecitabine. External radiotherapy will be based on contouring guidelines from the RTOG atlas and Radiation Therapy Oncology Group (RTOG 0822) with some modifications

* Oxaliplatin - 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* Leucovorin - bolus 400mg/m² following the oxaliplatin/FA infusions
* 5 Fluorouracil (5FU) - 2400 mg/m², 46-h infusion following the 5-FU bolus An outpatient, 46 hour continuous IV infusion provided by a home IV infusion company. The 5FU is delivered by a small pump worn in a fanny pack around the waist. The home IV infusion company will arrange your disconnect at the end of the infusion.

FOLFOX6

After the patient has been identified as a candidate for the trial, the surgeon will assess the patient and will determine:

Exact height and location of tumor with regards to the anal margin as measured by a rigid or flexible proctoscope and/or digital exam.

Mobility of tumor as assessed if possible by rectal exam Type of surgical procedure: Abdominoperineal resection vs. sphincter saving procedures, which will include colo-anal with mucosectomy vs. stapled anastomosis.

Surgery

Amol K Narang, M.D.

This research is being done to compare the effectiveness of high dose endorectal brachytherapy (END-HDR) and the standard treatment option of chemoradiation with Capecitabine in the treatment of cancer of the lowest part of the bowel (rectum).

Locally advanced rectal carcinoma continues to be a major oncologic problem in the United States with approximately 40,000 new cases diagnosed in 2011. For stage II/III rectal carcinoma, adjuvant chemoradiation and total mesorectal excision (TME) represent the major treatment advances that have increased cure rates over the past 30 years.

In the setting of TME, a landmark phase III German trial of stage II/III rectal cancer patients established neoadjuvant 5FU-based chemoradiation (NCRT) as standard of care over the same regimen given post-operatively. The preoperative arm showed superior local control (6% vs. 13% p=0.006), a complete pathologic response of 8%, a higher rate of sphincter preservation and less grade 3 toxicity compared to post-operative treatment. However, disease-free and overall survival (76% versus 74%, respectively) were no different because of the high rate of distant metastasis occurring in over 1/3 of patients (5yr DM 36 vs 38%,p=0.84). Importantly, those attaining a pathologic complete response had a decreased rate of distant metastasis and improved disease-free survival. Drawbacks to the regimen include acute grade 3 or 4 toxicity in 27% of patients, low compliance rates with postoperative chemotherapy (27 - 50%), and an overall decline in anorectal function shown by long-term studies.

Given the excellent locoregional control reported in TME surgical series, several trials have investigated whether certain patients may be spared preoperative radiotherapy. Two large randomized trials by Dutch and British investigators showed that a short preoperative course of hypofractionated EBRT (25 Gy in 5 fractions) followed by TME surgery decreased locoregional recurrence by 2/3 as compared to patients treated with TME surgery alone. In the Dutch trial, patients with mid and distal rectal cancers were most likely to benefit from radiotherapy. In these patients, preoperative radiation was shown to decrease locoregional recurrence by 5-fold (10% to 2%); however, the hypofractionated preoperative EBRT regimen was associated with a significant increase in acute and chronic morbidity. Indeed, the Dutch study revealed that irradiated patients, when compared to surgery alone, had more perineal wound healing problems after abdominoperineal resection (29% vs. 19%), worsening deterioration of anal sphincter dysfunction, and more severe long-term effects related to sexual functioning both in males (p=0.004) and females (p\<0.002). Additionally, colleagues have reported a consistent negative impact on bowel function in those patients undergoing sphincter preservation. In reviewing the long-term data of the Swedish short course preoperative EBRT rectal cancer trial, Birgisson also reported a higher incidence of secondary tumors (9.5%) in patients treated with preoperative radiation when compared to patients having surgery alone (4.3%).

Modern approaches to address the risk of distant metastasis and poor compliance with adjuvant systemic chemotherapy (following NCRT) have incorporated newer effective chemotherapy agents earlier in the treatment protocol. For example, oxaliplatin has been one of the most widely studied agents as a result of its proven efficacy when combined with 5-fluorouracil and leucovorin (FOLFOX) both in the metastatic and adjuvant settings for colon cancer. Initial phase II studies with the addition of oxaliplatin to standard 5-FU based NCRT appeared to show improved pathologic complete response rates compared to standard NCRT. However, two phase III trials clearly show that the addition of oxaliplatin during 5FU-based NCRT does not significantly improve pathologic complete response, locoregional control, distant metastasis or survival but does increase acute grade 3-4 toxicity by two to three-fold.

One approach to limit toxicity from external beam radiotherapy is the use of intensity modulated radiation therapy (IMRT). IMRT can limit radiation dose to normal rectum (above and below the tumor) and surrounding organs at risk (OARs) such as bladder and sexual organs. IMRT utilizes multiple beams of radiation to treat the rectal tumor plus a margin and limits dose to OARs. While IMRT decreases radiation dose to normal structures, it requires an additional 2-3 cm margin for microscopic extension (clinical treatment volume=CTV), set-up error, and rectal motion (planning treatment volume=PTV). Furthermore, IMRT still requires 5-6 weeks of radiation with concurrent chemotherapy, is substantially more expensive than conformal radiation, and is especially prohibitive in countries where access to technology necessary for IMRT is limited. Based on the preliminary results of RTOG 0822 and others, it still remains to be determined whether IMRT confers a statistically significant improvement in pCR, toxicity rates and QOL relative to standard NCRT.

A novel approach to limit radiation toxicity is the use of high dose rate endorectal brachytherapy (Endo-HDR). Endo-HDR involves the placement of a silicon multicatheter applicator within the rectum to deliver large doses to the rectal tumor and mesorectum with rapid dose fall off to the surrounding organs. An Iridium 192 high dose rate brachytherapy source attached to a wire is inserted into each catheter to deliver a high dose of radiation therapy the tumor. High dose rate brachytherapy has been well established in various malignancies (prostate, uterine, sarcoma, head and neck) to escalate radiation dose to the tumor over a short period of time while sparing normal tissue. Compared with NCRT and IMRT, Endo-HDR delivers treatment internally to the tumor without having to pass through surrounding normal tissue and organs. It requires smaller margins (CTV/PTV=\~1 cm) on the tumor since the applicator is positioned under fiducial guidance over the tumor without need for a margin for organ motion allowing greater sparing of OARs. Furthermore, the area of the rectum exposed to high dose radiotherapy is surgically removed at the time of resection which further minimizes chronic toxicity. Important structures that may be spared include bone marrow, small bowel, bladder, the autonomic nerves, sexual organs, anal sphincter and skin. Considering that 1/3 of patients will develop metastases, limiting bone marrow toxicity may contribute to better compliance with systemic treatment and allow for a better treatment strategy to target systemic recurrence. Another distinct advantage of Endo-HDR is the shortened treatment time (1 versus 6 weeks). Endo-HDR therefore provides a major logistic advantage for patients who may benefit from neoadjuvant therapy but who are geographically distant from radiation centers, elderly, or medically infirmed.

Chemoradiation or Brachytherapy for Rectal Cancer

Chemoradiation OR Brachytherapy for RECTal Cancer

Pathologic complete response rate is reported as the number of patients who achieve pathologic complete response after the treatment for each arm.

As per the NCCN guidelines, pathologic response is graded by the system recommended by the AJCC Cancer Staging Manual and CAP guidelines:

* Complete response - no remaining viable cancer cells
* Moderate response - only small clusters/single cancer cells remain
* Minimal response - residual cancer remaining, but with predominant fibrosis
* Poor response - minimal/no tumor kills, extensive residual cancer

Number of participants with grade 3 or higher adverse events will be listed by relationship.

Grading is by CTCAE 4 guidelines.

Relationship, as determined by PI, is unrelated/unlikely/possible/probable/definite.

Patients were given the EORTC QLQ-C30 at baseline, preop, postop, and at follow ups Y1-5. The forms were scored as per the manual available at EORTC. Raw scores are transformed to fall in a range of 0-100. Generally, higher scores on QoL scales represent higher levels of QoL.

The scores are reported as the mean of the Global Health Status/QoL scale score when more than 1 patient completed the form for a time point. If only 1 form was available for a time point, then the score for that form is reported.

Assessing the difference time to death rates among study participants.

Compare distant metastasis for both Endo-HDR and CRT.

Compare progression free survival for both Endo-HDR and CRT.

Compare locoregional control for both Endo-HDR and CRT.

Nucletron

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Patients will receive IMRT along with capecitabine.

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus Cycle length: 14 days (2 weeks); Duration of treatment: 12 cycles

Then: Surgical Resection capecitabine and IMRT (if randomized to this arm): Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy

IMRT (intensity modulated radiation therapy): Patients will receive IMRT along with capecitabine.

External radiotherapy will be based on contouring guidelines from the RTOG atlas and Radiation Therapy Oncology Group (RTOG 0822) with some modifications

FOLFOX6: \* Oxaliplatin - 85 mg/m² in 500ml glucose 5% solution, 2-h infusion

* Leucovorin - bolus 400mg/m² following the oxaliplatin/FA infusions
* 5 Fluorouracil (5FU) - 2400 mg/m², 46-h infusion following the 5-FU bolus

Surgery: After the patient has been identified as a candidate for the trial, the surgeon will assess the patient and will determine: Exact height and location of tumor with regards to the anal margin as measured by a rigid or flexible proctoscope and/or digital exam; Mobility of tumor as assessed if possible by rectal exam; Type of surgical procedure: Abdominoperineal resection vs. sphincter saving procedures, which will include colo-anal with mucosectomy vs. stapled anastomosis.

IMRT and Capecitabine

Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus Cycle length: 14 days (2 weeks); Duration of treatment: 12 cycles

Then: Surgical Resection:

Endo-HDR: Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

FOLFOX6: \* Oxaliplatin - 85 mg/m² in 500ml glucose 5% solution, 2-h infusion

* Leucovorin - bolus 400mg/m² following the oxaliplatin/FA infusions
* 5 Fluorouracil (5FU) - 2400 mg/m², 46-h infusion following the 5-FU bolus;

Surgery: After the patient has been identified as a candidate for the trial, the surgeon will assess the patient and will determine: Exact height and location of tumor with regards to the anal margin as measured by a rigid or flexible proctoscope and/or digital exam; Mobility of tumor as assessed if possible by rectal exam; Type of surgical procedure: Abdominoperineal resection vs. sphincter saving procedures, which will include colo-anal with mucosectomy vs. stapled anastomosis.

Endo-HDR

Patients will receive IMRT along with capecitabine.

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus Cycle length: 14 days (2 weeks); Duration of treatment: 12 cycles

Then: Surgical Resection

capecitabine and IMRT (if randomized to this arm): Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy

IMRT (intensity modulated radiation therapy): Patients will receive IMRT along with capecitabine.

External radiotherapy will be based on contouring guidelines from the RTOG atlas and Radiation Therapy Oncology Group (RTOG 0822) with some modifications

FOLFOX6: \* Oxaliplatin - 85 mg/m² in 500ml glucose 5% solution, 2-h infusion

* Leucovorin - bolus 400mg/m² following the oxaliplatin/FA infusions
* 5 Fluorouracil (5FU) - 2400 mg/m², 46-h infusion following the 5-FU bolus

Surgery: After the patient has been identified as a candidate for the trial, the surgeon will assess the patient and will determine:

Exact height and location of tumor with regards to the anal margin as measured by a rigid or flexible proctoscope and/or digital exam.

Mobility of tumor as assessed if possible by rectal exam Type of surgical procedure: Abdominoperineal resection vs. sphincter saving procedures, which will include colo-anal with mucosectomy vs. stapled anastomosis.

Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus Cycle length: 14 days (2 weeks); Duration of treatment: 12 cycles

Then: Surgical Resection

Endo-HDR (if randomized to this arm): Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

FOLFOX6: \* Oxaliplatin - 85 mg/m² in 500ml glucose 5% solution, 2-h infusion

* Leucovorin - bolus 400mg/m² following the oxaliplatin/FA infusions
* 5 Fluorouracil (5FU) - 2400 mg/m², 46-h infusion following the 5-FU bolus

Surgery: After the patient has been identified as a candidate for the trial, the surgeon will assess the patient and will determine: Exact height and location of tumor with regards to the anal margin as measured by a rigid or flexible proctoscope and/or digital exam.; Mobility of tumor as assessed if possible by rectal exam; Type of surgical procedure: Abdominoperineal resection vs. sphincter saving procedures, which will include colo-anal with mucosectomy vs. stapled anastomosis.

Total

Age, Categorical

Sex: Female, Male

white/caucasian

Race/Ethnicity, Customized

United States

Region of Enrollment

met baseline enrollment requirements as per protocol

Amol Narang, MD

Number of Patients With Pathologic Complete Response

Grade: 3; Relationship: probable

Grade: 3; Relationship: possible

Grade 3; Relationship: Unlikely

Number of Participants With Grade 3 or Higher Adverse Events

baseline

pre-op

post-op

year 1

year 2

year 3

year 4

year 5

3 patients randomised to IMRT arm had at least 1 form completed. 5 patients randomised to the ENDO arm had at least 1 form completed.

Change in EORTC QLQ-C30 Global Health Status Score

IMRT and Capecitabine (Potentially Randomized to This Arm)

Endo-HDR (Potentially Randomized to This Arm)

No patients were deceased during the study period.

Time to Death

No patients had metastases during study period.

Time to Distant Metastases Free Survival

No patients had progression during study period.

Time to Progression Free Survival

No patients had locoregional recurrence during study period.

Time to Local Disease Recurrence

Overall Study

Rare Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Neuroepithelioma

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

The therapeutic regimen will be divided into 2 different periods:

* Radiotherapy period The patient will start IMRT (60Gy/30fr/6 weeks), TMZ(Temozolomide) chemotherapy (75mg/m²/day), and olaparib on the same day, on a Monday (day 1), within 6 weeks after surgery. The daily dose of TMZ (75 mg/m²) will be continued until the end of radiotherapy (6 weeks) and olaparib will be continued with the same dose until 4 weeks after the end of IMRT, as a single agent.
* Maintenance period TMZ will then be re-introduced 4 weeks after the end of IMRT at the dose of 150 mg/m2/day on days 1 to 5 every 28 days, for a total of 6 cycles. Concomitantly, olaparib will be daily given at the maintenance dose level up to confirmed disease progression or unacceptable toxicities.

We propose 7 dose levels to reach the target dose of 400 mg per day (200 mg twice daily) of olaparib continuously

We propose 7 dose levels to reach the target dose of 400 mg per day (200 mg twice daily) of olaparib continuously DL1 (starting dose level) : Olaparib 50 mg Q12H Monday to wednesday DL2 : Olaparib 100mg Q12H Monday to wednesday DL3: Olaparib 100mg Q12H Monday to friday DL4 : Olaparib 200mg Q12H Monday to wednesday DL5: Olaparib 200mg Q12H Monday to friday DL6: Olaparib 200mg Q12H, continously

TMZ will be given at the dose of 75mg/m²/day during radiotherapy period. TMZ will be re-introduced 4 weeks after the end of radiotherapy at the dose of 150mg/m²/day on days 1 to 5 every 28 days, for a total of 6 cycles.

Temozolomide (TMZ)

Radiotherapy consists of fractionated focal irradiation at a dose of 2 Gy per fraction given once daily five days per week over 6 weeks, for a total dose of 60 Gy by 3D- Intensity-Modulated RT (IMRT)

IMRT (Intensity Modulated Radiation Therapy)

Dinu STEFAN, MD

Jean-Michel GRELLARD

Mathieu BOONE, MD

Mathieu BOONE

Paule AUGUREAU, MD

Charlotte BRONNIMANN, MD

Paul LESUEUR, MD

Violette ALLOUCHERY, MD

Edwina GIRARD, MD

Christian SIRE, MD

Marie-Pierre SUNYACH, MD

Julian JACOB, MD

Hamid MAMMAR, MD

Loic FEUVRET, PhD

Elodie VAULEON, MD

Cristina ALEXANDRU

Cristina ALEXANDRU, MD

Carole GOURMELON, MD

Elisabeth MOYAL COHEN-JONATHAN, Pr

The Stupp protocol is the standard treatment of glioblastoma multiform (GBM) which prognosis remains poor.

The non-dividing nature of normal brain cells provides an opportunity to enhance the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways such poly(ADP-ribose) polymerase (PARP) inhibitors, thus inducing more cytotoxic effects of DNA-damage related to treatment modalities, including alkylating reagents like temozolomide (TMZ).

Olaparib, a potent PARP inhibitor, overcomes apoptotic resistance and sensitizes GBM cells for death receptor-mediated apoptosis induced by TRAIL (Tumor necrosis factor-Related Apoptosis Inducing Ligand). Moreover, inhibition of PARP activity increases cellular sensitivity to ionizing radiation: it was even suggested to be more pronounced in tumors than in normal tissue.

Lastly, progress in technical imaging and intensity-modulated-radiotherapy (IMRT) techniques provide new possibilities for sparing healthy tissues.

HGGs are the most common and most aggressive primary brain tumor. There is a real need to improve care management of GBM patients. Attempts to achieve cure by increasing radiation dose result in unacceptable neurotoxicity. As for radiosensitizers, they can exacerbate normal tissue damage.

Since GBM represent a rapidly dividing cell population within the nonreplicating normal brain, the therapeutic ratio may be enhanced by specific radiosensitization of proliferating cells. Resistance to apoptosis is a paramount issue in the treatment of HGG. Targeting PARP by the inhibitors like olaparib can reduce proliferation and lowers the apoptotic threshold of HGG (effect showed in vivo and in vitro).

In this context, we propose a phase I-IIa trail to investigate the toxicity and efficacy of olaparib and TMZ concomitantly with radiotherapy in first line treatment of unresectable high risk HGG.

Correlation between treatment response and tumor profiling will allow us to identify biomarkers that can be useful in treatment improvement and/or present a prognostic value. Then, the transfer of this approach will be evaluated in terms of compatibility with the requirements of diagnostic.

Phase I/IIa Study of Concomitant Radiotherapy With Olaparib and Temozolomide in Unresectable High Grade Gliomas Patients

The primary objective for the phase I is to determine the Recommended Phase II Dose (RP2D) of olaparib combined with the Stupp protocol (TMZ and concomitant fractionated radiotherapy: 60Gy/30 fractions/6 weeks) in first line treatment of patients with unresectable high-grade gliomas

The primary objective for the phase II is to assess the 12-month overall survival of the combination

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab Plus Olaparib in LA-HNSCC	NCT05366166	Squamous Cell C...	Pembrolizumab Olaparib Cisplatin IMRT (intensity...	18 Years -	UNC Lineberger Comprehensive Cancer Center
Chemoradiation or Brachytherapy for Rectal Cancer	NCT02017704	Rectal Cancer	Endo-HDR (if ra... capecitabine an... IMRT (intensity... FOLFOX6 Surgery	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Chemoradiation or Brachytherapy for Rectal Cancer	NCT02017704	Rectal Cancer	Endo-HDR (if ra... capecitabine an... IMRT (intensity... FOLFOX6 Surgery	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Chemoradiation or Brachytherapy for Rectal Cancer	NCT02017704	Rectal Cancer	Endo-HDR (if ra... capecitabine an... IMRT (intensity... FOLFOX6 Surgery	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Phase I/IIa Study of Concomitant Radiotherapy With Olaparib and Temozolomide in Unresectable High Grade Gliomas Patients	NCT03212742	Malignant Gliom... Radiotherapy PARP Inhibitor	Olaparib Temozolomide (T... IMRT (Intensity...	18 Years - 70 Years	Centre Francois Baclesse
Chemoradiation or Brachytherapy for Rectal Cancer	NCT02017704	Rectal Cancer	Endo-HDR (if ra... capecitabine an... IMRT (intensity... FOLFOX6 Surgery	18 Years - 100 Years	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Spots Global Cancer Trial Database for imrt (intensity modulated radiation therapy)