Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Seroma

Breast Diseases

Skin Diseases

Winkle A Kwan, MD

Markings placed on the skin are an accurate representation of the underlying surgical cavity and are adequate to use for patient setup for accelerated partial breast irradiation.

1. Purpose - A feasibility study to determine the accuracy of using skin markings as a surrogate for the underlying surgical cavity (SC) in accelerated partial breast irradiation.
2. Hypothesis - Markings placed on the skin are an accurate representation of the underlying surgical cavity and are adequate to use for patient setup for accelerated partial breast irradiation.
3. Justification Breast conserving surgery with the use of whole breast radiation after partial mastectomy is the preferred treatment for most women with early stage breast cancer. Conventional radiotherapy in this setting delivers radiation to the entire breast, with the consequence that the radiotherapy has to be given over a period of 3 - 6 weeks. However, the majority (70 - 80%) of local recurrences after breast conserving surgery develop in the vicinity of the primary tumor. Partial breast irradiation with the radiation target volume limited to the surgical cavity (SC) in selected patients is therefore potentially feasible if it results in similar local control rates compared to whole breast irradiation. In addition to limiting the radiation to breast tissue most likely to harbor microscopic disease and thereby sparing the normal breast tissue, local breast irradiation offers the distinct advantage of shortening the duration of radiotherapy, thereby minimizing the impact radiotherapy has on the quality of life of breast cancer patients.

   The current technique for accelerated partial breast irradiation assumes that the cutaneous markers correctly reflect the position of the underlying SC without strong evidence that the relationship between the two does not change. Our study will provide the crucial missing link. Phase II of our study (not included in this REB application) will go further in exploring the use of new imaging modalities in reducing the PTV margins thereby enabling oncologists to better spare normal tissues.
4. The primary objective is to determine whether skin markings truly reflect the surgical cavity location during daily treatment by quantifying any change in relationship between the skin markings \& the surgical cavity.

   The secondary objective is to investigate the dosimetric consequences of the change in size, shape, and location of the surgical cavity volume (SCV) during the treatment duration.
5. Methods (for details see the attached protocol) To determine whether skin markings truly reflect the surgical cavity location during daily APBI.

Briefly, for Stage 1 of the study, 20 breast cancer patients undergoing adjuvant radiotherapy after breast conserving surgery with a visible SC (cavity visualization score 3 - 5) will be recruited. Skin markers will be placed on the skin around the SC during CT simulation in the manner specified in the RAPID trial. During the first week of their treatment, patients will return to the CT scanner on days 1 and 5 to undergo repeat planning CT. The patients will be set up simulating the actual treatment set up at the linear accelerator. These repeat scans will be compared with the original scan to identify any change in the relationship between the skin markings and the SC. Five oncologists trained in SC identification will then contour the SC on the original as well as the repeat CT scans. These images will be fused for each CT scan to form a representative SC volume (RSCV). The RSCV in planning and subsequent CTs will be related to skin marks to evaluate the reliability of patient positioning. Using these skin marks the beams will be placed on the patient in the CT simulation software package.

The centre of mass (COM) from RSCV will be determined from the contours and variations in x,y, and z coordinates will be averaged. This will allow a comparison between what was planned originally and what has changed over time. Coordinates of previously placed skin markers on the breast surface will be calculated relative to the COM as well as medial and lateral tattoos. This will enable us to verify if setup to external skin marks track the RSCV.

The dosimetric consequences of SCV changes in shape/size/location will be quantified as follows:

1. Repeat CTs with drawn RSCVs will be exported to the planning system and planning fields will be applied to calculate dose distributions in target volumes and organs at risk.
2. Dose-volume histograms (DVH) for CTV, PTV and organs at risk, as defined from CT will be evaluated for meeting planning criteria.
3. The procedure will be repeated with simulated patient realignment using CT data sets.
4. Appropriate PTV margins to achieve desired CTV coverage will be calculated for both the situations, with and without simulated realignment.

6. Statistical Analysis Sample Size: For Stage I, 20 patients can be successfully accrued in 6 months at the Fraser Valley Cancer Centre.

Comparison between skin marks and surgical cavity

The centre of mass (COM) from RSCV will be determined and the mean variations in x,y, and z coordinates will be calculated. In addition, the mean and standard deviation of the change in volume of the RSCV will be calculated. The movement of the COM coordinates will be calculated in reference to both the tattoos and the point guards separately. A paired t-test will be used to assess whether there is a statistically significant difference in mean COM movement in reference to the tattoos and centre spots. This will allow us to verify if setup to external skin marks (tattoos and point guards respectively) track the RSCV.

DVH comparison

The dosimetric consequences of changes in shape, size, and location of the RSCV will be quantified through analysis of DVHs (see section 7.5.). Descriptive statistics will be used to present the change in DVH for target volumes (CTV, PTV, and DEV) and OAR that occurred between the initial simulated plan and the 5 additional simulated plans (see sections 7.2 through 7.5). Furthermore, this will be repeated for the plans that have undergone simulated realignment. A paired t-test will be used to assess whether there is a statistically significant difference in mean change in DVH (for target volumes and OAR) before and after simulated realignment.

Potential decrease in CTV to PTV margin

The margin required on the CTV to create a PTV which ensures it is adequately covered, will be obtained using the DVH criteria in Table 2. Subsequently, this will be repeated for the plans that have undergone simulated realignment. A paired t-test will be used to assess whether there is a statistically significant difference in mean change in the CTV margin needed before and after simulated realignment.

Simulated patient realignment compensates for a portion of the CTV to PTV margin (the size, shape and position of the RSCV) while still leaving some uncertainty (e.g., patient respiration, daily setup). Therefore it is hypothesized that we can decrease the PTV needed with simulated realignment. We will consider a decrease in the PTV margin by ≥ 3 mm with simulated patient realignment justification for progression to Stage II of this study.

Do Skin Markings Reflect the Location of the Surgical Cavity During Daily Radiotherapy Treatment?

Development of Improved Target Volume Localization for Accelerated Partial Breast Irradiation- Stage I

British Columbia Cancer Agency

Radiation Oncologist

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Neuroendocrine Tumors

Carcinoid Tumor

Intestinal Neoplasms

Pancreatic Neoplasms

Stomach Neoplasms

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Stomach Diseases

Neuroendocrine Tumor

Gastro-enteropancreatic Neuroendocrine Tumor

Pancreatic Neuroendocrine Tumor

Pancreatic Cancer

Stomach Cancer

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Gastrointestinal Agents

Anti-Infective Agents

Everolimus

Somatostatin

Sunitinib

Octreotide

Lanreotide

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Antineoplastic Agents, Hormonal

Part 1 is an uncontrolled dose de-escalation study to confirm the safety and determine the RP3D of RYZ101 based on Bayesian optimal interval design. Eligible participants will be enrolled in cohorts of 6 to receive RYZ101 up to 4 infusions every 8 weeks. If the initial dose level is not tolerated, the dose will be de-escalated; up to 3 dose levels will be assessed.

Actinium 225 radiolabeled somatostatin analog (SSA) for injection

Investigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide.

RYZ101

Everolimus 10 mg

Sunitinib 37.5 MG

High-dose octreotide LAR 60 mg Q4W by i.m. injection

Octreotide LAR 60 MG Injection

High dose frequency lanreotide 120 mg Q2W by deep s.c. injection

Lanreotide 120Mg Sa Susp Inj Syringe

Denis Ferreira, MD

This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin receptor expressing (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with Lutetium 177-labelled somatostatin analogue (177Lu-SSA) therapy, such as 177Lu-DOTATATE or 177Lu-DOTATOC (177Lu-DOTATATE/TOC), or 177Lu-high affinity \[HA\]-DOTATATE.

Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy

Phase 1b/3 Global, Randomized, Controlled, Open-label Trial Comparing Treatment With RYZ101 to Standard of Care Therapy in Subjects With Inoperable, Advanced, SSTR+, Well-differentiated GEP-NETs That Have Progressed Following Prior 177Lu-SSA Therapy

Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings

Relationship between biomarkers, including but not limited to CgA in the serum and (5-HIAA) in the urine, with AEs of special interest and/or efficacy endpoints (e.g., PFS, OS, BOR, DoR)

Measured by continuous ECG recording using a 12-lead Holter monitoring device

Incidence of DLTs during the first 56 days of study treatment will be assessed.

PFS will be defined as the time from the date of randomization until the date of progression (as determined by BICR from tumor assessments using RECIST v1.1) or death due to any cause, whichever occurs earlier.

Calculated mean TIAC (hours) and absorbed radiation dose coefficients (mGy/MBq) to critical organs (e.g., the kidneys and bone marrow) and tumors after the 1st and 4th RYZ101 infusions will be assessed

OS will be defined as the time from the date of randomization until the date of death due to any cause.

ORR, as determined by BICR according to RECIST v1.1.

ORR, as assessed by the Investigator according to RECIST v1.1

Assessed by BICR and by the Investigator according to RECIST v1.1

Only for subjects with a RECIST v.1.1 response, assessed by BICR and by the Investigator according to RECIST v1.1

RayzeBio, Inc.

Blood and Lymph Conditions

Immune System Diseases

Heart and Blood Diseases

Leukemia

Lymphoma

Multiple Myeloma

Neoplasms, Plasma Cell

Hematologic Neoplasms

Hematologic Diseases

Chronic Graft Versus Host Disease

Lymphosarcoma

Acute Graft Versus Host Disease

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Patients receive therapy with an yttrium-90 labelled anti-CD66 following favourable dosimetry with the same antibody radiolabelled with indium-111.

Yttrium-90 labelled anti-CD66 monoclonal antibody.

Targeted radiotherapy

Kim H Orchard, MBBS PhD

To determine whether a radiolabelled antibody that targets the bone marrow (the 'anti-CD66') can be administered safely to patients as part of the preparative treatment prior to haematopoietic stem cell transplantation ('a bone marrow transplant'). Can the radiolabelled antibody be shown to effectively target the bone marrow in these patients. If it can, could this result in better outcomes after transplantation.

The aim of this clinical research study is to establish whether a radiolabelled antibody can be used to safely deliver radiotherapy to the bone marrow prior to stem cell transplantation for haematological malignancies.

With current chemotherapy regimens 60-90% of adult patients with acute leukaemia (AML and ALL) achieve a complete remission. However in a significant proportion of these patients the disease will recur. Although allogeneic and autologous bone marrow or peripheral blood haematopoietic stem cell transplantation (HSCT) are established as effective treatment options for haematological malignancies, resulting in long term disease free survival in a significant proportion of patients, the results of transplantation for patients with poor risk disease are disappointing. Further intensification of the treatment used prior to transplantation has been shown to reduce the risk of relapse, but the toxicity of the drugs or external beam radiotherapy causes an increase in transplant related deaths. The introduction of reduced intensity conditioning protocols allows the use of HSCT for older patients or those with significant additional medical problems but retrospective analysis indicates an increased rate of relapse. This is the 'Transplantation dilemma' - how to reduce the risk of disease relapse by intensifying therapy, but without an increase in toxicity to other organs causing an increase in transplant related deaths in remission.

Normal haematopoietic tissue and the malignant cells arising from it are very radiosensitive. Theoretically intensification of the conditioning therapy, particularly total body irradiation (TBI), prior to transplantation could increase tumour reduction leading to improved disease free survival rates for patients with poor risk disease. Targeted radiotherapy could allow treatment intensification without the toxicity to non-haematological tissues. In addition, the continuous, low dose rate delivered by the natural decay of a targeted radionuclide may have a greater destructive effect upon tumour cells than single dose or fractionated external beam radiation.

Targeted Radiotherapy in HSCT for Poor Risk Haematological Malignancy

Radiolabelled Anti-CD66 Monoclonal Antibody in the Conditioning Regimen Prior to Haematopoietic Stem Cell Transplantation: Phase I Study in Patients With Poor-risk Disease.

Trial fully recruited. Data will be summarised upon completion of study.

To determine the maximum tolerated dose (MTD) of targeted radiotherapy delivered by a murine anti-CD66 monoclonal antibody radiolabelled with yttrium-90 (Y-90) and determine the dose-limiting toxicity (DLT) in patients with haematological malignancies who are undergoing haematopoietic stem cell transplantation.

Toxicities are assessed using WHO Toxicity Scale with 28 parameters.

Dosimetry is determined by whole body and SPECT-CT of the thorax and abdomen on days 1, 2, 4 and 5 post infusion of an indium-111 radiolabelled anti-CD66. Dosimetry determines whether patients proceed to therapy with the yttrium-90 labelled anti-CD66.

Royal Free and University College Medical School

University Hospital Southampton NHS Foundation Trust

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Small Cell Lung Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Small Cell Lung Cancer

Etoposide

Carboplatin

Atezolizumab

Etoposide phosphate

Radiopharmaceuticals

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

RYZ101 (Actinium 225 radiolabeled somatostatin analog (SSA)) 6.5 MBq/175 μCi in combination with standard of care (SoC) carboplatin + etoposide + atezolizumab

6.5 MBq/175 μCi administered by IV for up to 6 infusions once every 4 or 6 weeks

RYZ101 Dose Level 1

8.3 MBq/225 μCi administered by IV for up to 6 infusions once every 4 or 6 weeks

RYZ101 Dose Level 2

10.2 MBq/275 μCi administered by IV for up to 6 infusions once every 4 or 6 weeks

RYZ101 Dose Level 3

4.6 MBq/125 μCi administered by IV for up to 6 infusions once every 4 or 6 weeks

RYZ101 Dose Level -1

1200 mg administered IV for 4 x 21-day cycles, followed by 1680 mg every 28-days (maintenance)

AUC 5-6 administered IV for 4 x 21-day cycles

80-100 mg/m2 administered IV on 3 consecutive days for 4 x 21-day cycles

RayzeBio Clinical Trials

Jonathan Goldman

Megan Gee

Claire Mulvey, MD

Ephraim Parent, MD

Caitlin Mynard

Justin Rineer, MD

Mark Crystal

Manish Thakur, MD

Heather Austin

Krisha Howell, MD

Aaron Mansfield, MD

Marlene Bridwell

Robert Langdon, MD

John Waldron

John Waldron, MD

Sonam Puri, MD

Iris G. Garcia-Acevedo, BSN-RN

Noridza Rivera-Rodriguez, MD

Denise Ferreira, MD

This study aims to determine the safety, preliminary antitumor activity, and pharmacokinetics (PK) of RYZ101 in combination with standard of care (SoC) therapy consisting of carboplatin + etoposide + atezolizumab in untreated subjects with somatostatin receptor expressing (SSTR+) ES-SCLC.

Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC

Phase 1b Single Arm, Open-label Trial of RYZ101 in Combination With Carboplatin + Etoposide + Atezolizumab in Subjects With Somatostatin Receptor Expressing (SSTR+) Extensive Stage Small Cell Lung Cancer (ES-SCLC)

RP2D as determined by incidence rate of DLTs

Safety and tolerability of RYZ101 in combination with SoC as measured by incidence and severity of AEs including SAEs, laboratory changes and other safety findings

Durable ORR defined as the proportion of subjects with measurable disease at baseline who achieve confirmed CR or PR according to RECIST v1.1 lasting at least 4 months

ORR as assessed by the Investigator according to RECIST v1.1

Only for subjects with a RECIST v.1.1 response, assessed by the Investigator according to RECIST v1.1

OS as defined from the time of first dose of RYZ101 or first dose of SoC therapy to the date of death due to any cause

BOR as assessed by the Investigator according to RECIST v1.1

Disease control rate (PR + CR + SD) as assessed by the Investigator according to RECIST v1.1

PFS as defined from date of first dose of RYZ101 or first dose of SoC therapy to the date of progression as assessed by the Investigator according to RECIST v1.1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Do Skin Markings Reflect the Location of the Surgical Cavity During Daily Radiotherapy Treatment?	NCT00578747	Breast Cancer		-	British Columbia Cancer Agency
Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy	NCT05477576	GEP-NET Gastroenteropan... Gastroenteropan... Neuroendocrine ... Carcinoid Carcinoid Tumor Pancreatic NET	RYZ101 Everolimus 10 m... Sunitinib 37.5 ... Octreotide LAR ... Lanreotide 120M...	18 Years -	RayzeBio, Inc.
Targeted Radiotherapy in HSCT for Poor Risk Haematological Malignancy	NCT01521611	Acute Leukaemia Chronic Leukaem... Myeloma Lymphoma	Targeted radiot...	18 Years - 75 Years	University Hospital Southampton NHS Foundation Trust
Study of RYZ101 in Combination With SoC in Subjects With SSTR+ ES-SCLC	NCT05595460	SCLC,Extensive ...	RYZ101 Dose Lev... RYZ101 Dose Lev... RYZ101 Dose Lev... RYZ101 Dose Lev... Atezolizumab Carboplatin Etoposide	18 Years -	RayzeBio, Inc.

Spots Global Cancer Trial Database for targeted radiotherapy